EP0379441A1 - Benzopyrane derivatives, their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

New benzopyran derivatives of general formula (I) in which: - R1 represents a hydrogen or halogen atom or a hydroxy, alkyloxy, nitro, amino, alkylsulfonamido or acylamino radical, - R represents 1) a radical <IMAGE> R2 and R3, identical or different, being H, halogen, OH, alkyl, alkyloxy, NH2, alkylsulfonamido or NO2, or, 2) an <IMAGE> radical n being 0 or 1, R4 being H, alkyl or phenyl optionally substituted and Q is acyl, alkylsulfonyl, or <IMAGE> Y being -CO- or -SO2- and Z being a single bond, -CH2- or -NH-, or, 3) a radical <IMAGE> n being 0 or 1, m being 0 or 2, X being C or N (if n = 0), W being a bond or -NH- and Ar being pyridyl, indolyl, quinolyl, 2-alkyl quinolyl or phenyl optionally substituted by R2 and R3, provided that n = O when X is N or, 4) a radical of general formula: <IMAGE> R7 being H or alkyl, or else, 5) a radical <IMAGE> - R 'and R "are identical and represent s hydrogen atoms or alkyl radicals, their isomeric forms and mixtures thereof, their addition salts with acids. These new products are useful as antiarrhythmic and anti-fibrillants. <IMAGE>

Description

leurs sels, leur préparation et les compositions pharmaceutiques qui les contiennent.The present invention relates to new benzopyran derivatives of general formula:

their salts, their preparation and the pharmaceutical compositions containing them.

dans laquelle

• - A représente notamment une liaison simple,
• - R₁, R₂, R₈, R₉, R₁₀ et R₁₁ peuvent représenter des atomes d'hydrogène,
• - R₃, R₄, Rs et R₆ peuvent être des atomes d'hydrogène ou des radicaux alcoyloxy,
• - R₁₂ à R₁₆ peuvent être entre autres des atomes d'hydrogène, des radicaux alcoyloxy ou 2 de ces radicaux adjacents peuvent former un radical méthylènedioxy,
• - et -NR₇-CR₈R₉-CR₁₀R₁₁-X- peut représenter un radical pipérazinyle.

In the German patent application 3 300 004 were described derivatives of 4-aminomethyl benzopyran active as hypotensive and muscle relaxants, and corresponding to the formula:

in which

• - A represents in particular a single bond,
• - R ₁ , R ₂ , R ₈ , R ₉ , R ₁₀ and R ₁₁ may represent hydrogen atoms,
• - R ₃ , R ₄ , Rs and R ₆ may be hydrogen atoms or alkyloxy radicals,
• - R ₁₂ to R ₁₆ may be, inter alia, hydrogen atoms, alkyloxy radicals or 2 of these adjacent radicals may form a methylenedioxy radical,
• - and -NR ₇ -CR ₈ R ₉ -CR ₁₀ R ₁₁ -X- may represent a piperazinyl radical.

• - R₁ représente un atome d'hydrogène ou d'halogène ou un radical hydroxy, alcoyloxy, nitro, amino, alcoylsulfonamido ou acylamino,
• - R représente
  • 1) un radical de formule générale :
    
    dans laquelle R₂ et R₃ identiques ou différents représentent des atomes d'hydrogène ou d'halogène ou des radicaux hydroxy, alcoyle, alcoyloxy, amino, alcoylsulfonamido ou nitro, ou bien
  • 2) un radical de formule générale :
    
    dans laquelle n égale 0 ou 1, R₄ est un atome d'hydrogène, un radical alcoyle ou un radical de structure :
    
    dans laquelle R_s et R_s sont des atomes d'hydrogène ou d'halogène ou un radical alcoyloxy et Q représente un radical acyle, alcoylsulfonyle ou un radical de structure :
    
    dans laquelle R₂ et R₃ sont définis comme ci-dessus, Y représente un radical carbonyle ou sulfonyle et Z représente une liaison simple ou un radical méthylène ou imino, ou bien
  • 3) un radical de formule générale :
    
    dans laquelle n égale 0 ou 1, m égale 0 à 2, X est un atome de carbone ou X peut être un atome d'azote si n = 0, W représente une liaison simple ou un radical imino et Ar représente un radical pyridyle, indolyle, quinolyle, alcoyl-2 quinolyle ou Ar représente un radical phényle éventuellement substitué par des radicaux R₂ et R₃ tels que définis ci-dessus, à condition que m soit autre que O lorsque X est un atome d'azote, ou bien
  • 4) un radical de formule générale :
    
    dans laquelle R₂ et R₃ sont définis comme précédemment et R₇ représente un atome d'hydrogène ou un radical alcoyle, ou bien
  • 5) un radical de formule :
    
• - R' et R identiques représentent des atomes d'hydrogène ou des radicaux alcoyle, ainsi que leurs sels, entraînent notamment une augmentation des périodes réfractaires particulièrement intéressante qui correspond aux effets antifibrillants des produits antiarythmiques de la classe III selon la classification de VAUGHAN WILLIAMS.

It has been found that the products of general formula (I) in which

• R ₁ represents a hydrogen or halogen atom or a hydroxy, alkyloxy, nitro, amino, alkylsulphonamido or acylamino radical,
• - R represents
  • 1) a radical of general formula:
    
    in which R ₂ and R _{3, which are} identical or different, represent hydrogen or halogen atoms or hydroxy, alkyl, alkyloxy, amino, alkylsulfonamido or nitro radicals, or else
  • 2) a radical of general formula:
    
    in which n equals 0 or 1, R ₄ is a hydrogen atom, an alkyl radical or a radical of structure:
    
    in which R _s and R _s are hydrogen or halogen atoms or an alkyloxy radical and Q represents an acyl, alkylsulfonyl radical or a radical of structure:
    
    in which R ₂ and R ₃ are defined as above, Y represents a carbonyl or sulfonyl radical and Z represents a single bond or a methylene or imino radical, or alternatively
  • 3) a radical of general formula:
    
    in which n equals 0 or 1, m equals 0 to 2, X is a carbon atom or X can be a nitrogen atom if n = 0, W represents a single bond or an imino radical and Ar represents a pyridyl radical, indolyl, quinolyl, 2-alkyl-quinolyl or Ar represents a phenyl radical optionally substituted by radicals R ₂ and R ₃ as defined above, provided that m is other than O when X is a nitrogen atom, or else
  • 4) a radical of general formula:
    
    in which R ₂ and R ₃ are defined as above and R ₇ represents a hydrogen atom or an alkyl radical, or else
  • 5) a radical of formula:
    
• - R 'and R identical represent hydrogen atoms or alkyl radicals, as well as their salts, in particular cause an increase in refractory periods which is particularly advantageous which corresponds to the anti-fibrillating effects of antiarrhythmic products of class III according to the classification of VAUGHAN WILLIAMS.

In the general formula (1), when R ₁ and / or R ₂ , R ₃ , Rs or R ₆ (in the symbol R) represent a halogen atom, this can be chosen from fluorine, chlorine, bromine or iodine. In addition, it is understood that the radicals and alkyl or acyl portions may be straight or branched and contain 1 to 4 carbon atoms.

It is also understood that the products of general formula (I) have isomeric forms and that these isomers and their mixtures fall within the scope of the present invention.

dans laquelle R₁, R et R sont définis comme précédemment et Y₁ représente un atome d'halogène ou un radical alcoylsulfonyloxy ou arylsulfonyloxy suivie éventuellement de l'oxydation du produit obtenu, lorsque l'on veut préparer un produit pour lequel n = 1, ou bien de la transformation en oxime lorsque l'on veut obtenir un produit pour lequel R est un radical défini précédemment en 4) et lorsque l'on a obtenu la cétone correspondante pour laquelle R est un radical défini précédemment en 3) m étant égal à O et - W - Ar étant un radical phényle éventuellement substitué.According to the invention, the products of general formula (I) can be obtained by the action of a product of general formula:
H - R (VIII)
or its salt, in which R is defined as above, provided that n = 0, on a benzopyran derivative of general formula:

in which R ₁ , R and R are defined as above and Y ₁ represents a halogen atom or an alkylsulfonyloxy or arylsulfonyloxy radical optionally followed by the oxidation of the product obtained, when it is desired to prepare a product for which n = 1 , or transformation into oxime when it is desired to obtain a product for which R is a radical defined previously in 4) and when the corresponding ketone has been obtained for which R is a radical defined previously in 3) m being equal to O and - W - Ar being an optionally substituted phenyl radical.

It is advantageously carried out in the presence of an acid accepting agent. It is also possible to operate without an acid acceptor, in the presence of 2 equivalents of the product of general formula (VIII).

When Y ₁ represents a halogen atom, it can be chosen from chlorine or bromine atoms.

When Y ₁ represents an alkylsulfonyloxy radical, it represents in particular the methylsulfonyloxy radical and when it represents an arylsulfonyloxy radical, it can be inter alia the p.toluenesulfonyloxy radical.

As an acid acceptor, an alkali or alkaline earth metal hydroxide (sodium hydroxide or potassium hydroxide for example) is advantageously used, an alkali metal carbonate (sodium bicarbonate, potassium carbonate for example), or an organic nitrogenous base such as triethylamine for example.

The reaction is carried out in an inert solvent such as a ketone (acetone, butanone for example), an ether (tetrahydrofuran or dioxane for example), an alcohol (methanol or ethanol for example), a hydrocarbon (hexane or toluene for example ), acetonitrile, dimethylformamide or dimethylsulfoxide, or in a mixture of such solvents, at a temperature between 20 ° C. and the reflux temperature of the reaction mixture.

It is understood that in the cases where Ri, R ₂ and / or R ₃ (in R) represent an amino radical, the latter is previously protected. Similarly when R ₂ and / or R ₃ represent a hydroxy radical, it is preferable to protect this radical before the reaction.

Protection is carried out by any compatible grouping, the implementation and disposal of which do not alter the rest of the molecule. In particular, one operates according to the methods described by TW Greene, Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication (1981), or by Mc Omie, Protective Groups in Organic Chemistry, Plenum Press (1973).

Where appropriate, the oxidation is carried out by any known method which does not alter the rest of the molecule. The reaction is carried out in particular by means of an oxidizing agent such as an organic peracid, for example peracetic acid or monoperphthalic acid, in an organic solvent such as an ether (ethyl ether, tetrahydrofuran for example) or a chlorinated solvent (chloroform, dichloromethane for example) at a temperature between 0 and 25 C. Oxidation can also be carried out using hydrogen peroxide by operating in an aqueous medium or in acetic acid or acetic anhydride at a temperature between -50 and + 25 ° C.

It is understood that, in the case where the molecule carries amino substituents, the oxidation is carried out before the release of the protective radicals.

Where appropriate, the transformation into a product for which R is a radical of general formula (VI) in which R ₇ is a hydrogen atom or an alkyl radical, is carried out by the action of hydroxylamine hydrochloride or O -alkylhydroxylamine.

It is generally carried out in the presence of a base (soda for example) in an alcohol (absolute ethanol) at a temperature between 20 and 80 C.

According to the invention, the products of general formula (I) for which the radicals Ri, R ₂ and / or R ₃ represent a hydroxy radical can also be obtained from the corresponding product of general formula (I) for which the radical Ri , R ₂ and / or R ₃ to be transformed represents an alkyloxy radical, by treatment in concentrated acid medium.

The reaction is generally carried out by treatment with hydrobromic acid, or a mixture of acids, for example by treatment with a hydrobromic acid-acetic acid mixture, at the reflux temperature of the reaction mixture.

According to the invention, the products of general formula (I) for which R is defined as above in 1) and 2), and the symbols Ri, R ₂ and / or R ₃ represent an amino or alkylsulfonamido radical or for which R ₁ represents an acylamino radical, can also be obtained by catalytic hydrogenation in acid medium of the corresponding benzopyran derivative of general formula (I) for which the radical Ri, R ₂ and / or R ₃ to be transformed represents a nitro radical, then when the we want to obtain a product of general formula (I) for which R 1, R ₂ and / or R ₃ represent an alkylsulphonamido radical or for which R ₁ is an acylamino radical, the amino derivative obtained is converted respectively by sulphonylation or by acylation.

The hydrogenation is advantageously carried out at a temperature between 20 and 50 ° C., in an acid such as, for example, acetic acid or hydrochloric acid, in an organic solvent such as an alcohol (methanol, ethanol, isopropanol for example ) in a mixture of solvents, or in a hydroorganic medium (alcohol - water for example). It is also possible to operate directly in the acid, without additional addition of a solvent.

Palladium, platinum oxide or Raney nickel are generally used as catalyst.

Optionally, it operates under pressure.

The sulfonylation or the acylation is carried out respectively by the action of an activated form of an acid alkSO ₃ H or alk'COOH (alk and alk; being alkyl radicals), in particular the acid halide (chloride of acid for example) or anhydride, and the operation is carried out in the presence of an acid acceptor such as a nitrogenous organic base such as a trialkylamine (triethylamine for example) or like pyridine, in an inert organic solvent such as '' a chlorinated solvent (dichloromethane, chloroform for example), an ether (ethyl ether, tetrahydrofuran for example) or in a mixture of these solvents, at a temperature between -70 and + 40 ° C.

Optionally, we operate under nitrogen.

ou

dans laquelle R₂, R₃, W, Ar et m sont définis comme précédemment, et Hal est un atome d'halogène choisi parmi le chlore ou le brome sur un dérivé du benzopyranne de formule générale :

dans laquelle Ri, R et R" sont définis comme précédemment.According to the invention, the products of general formula (I) for which R is defined as above in 1) and 3) when X is a nitrogen atom, can also be prepared by the action of a halide of structure:

or

in which R ₂ , R ₃ , W, Ar and m are defined as above, and Hal is a halogen atom chosen from chlorine or bromine on a benzopyran derivative of general formula:

in which Ri, R and R "are defined as above.

It is understood that, when R ₁ , R ₂ and / or Rs represent amino or hydroxyl radicals, these are protected before the reaction.

The protection and elimination of the protective radicals is carried out under the conditions described above for the process which consists in reacting the products of general formula (VIII) and (IX).

When a product of general formula (Xa) or (Xb) in which m = 0 is acted, one operates either in an organic medium, optionally in the presence of an acid acceptor such as a nitrogenous organic base (for example a trialkylamine or a pyridine) in a solvent as mentioned above, or a mixture of these solvents at a temperature between 0 and 20 C, either in a hydroorganic medium in the presence of an alkaline condensing agent such as carbonate or bicarbonate of alkali or alkaline earth metal, at a temperature between 5 and 20 ^° C.

When a product of general formula (Xb) for which m is 1 or 2 is made to act, the procedure is carried out under the conditions described above to prepare a product of general formula (I) from the products of general formulas (VIII) and (IX).

• - lorsque R est défini comme précédemment en 1) ou 3), X étant un atome d'azote : par action d'un dérivé halogéné de formule (Xa) ou (lXb) sur la pipérazine dans les conditions décrites précédemment pour la réaction des produits de formule générale (VIII) avec un dérivé du benzopyranne de formule générale (IX) en présence d'un excès de pipérazine, sans addition supplémentaire d'un accepteur d'acide ;
• - lorsque R est défini comme en 2) : selon la méthode décrite dans le brevet français M 2430, ou selon les méthodes mentionnées par Anwer Basha, Tet. Lett., 29(21), 2525 (1988) ;
• - lorsque R est défini comme en 3), X étant un atome d'azote et W un radical imino : à partir d'une benzylpipérazine, par application des méthodes mentionnées par Anwer Basha, Tet. Lett., 29(21), 2525 (1988) puis de l'élimination du radical protecteur de la pipérazine;
• - lorsque R est défini comme en 3), X étant un atome de carbone,
  • a) si W est une liaison : par réaction de Friedel et Crafts entre un chlorure d'acide de formule générale :
    
    dans laquelle m égale 1 ou 2, et un produit de formule générale :
    
    dans laquelle R₂ et R₃ sont identiques ou différents et représentent des atomes d'hydrogène, d'halogène ou un radical amino préalablement protégé, ou par application de la méthode décrite par P. Rabbe, Ber., 55, 532 (1922) ;
  • b) si W est un radical imino : par application de la méthode décrite par L.D. Wise et coll., J. Med. Chem., 28, 606 (1985) ;
• - lorsque R est défini comme en 5) : selon la méthode décrite par A. Quevauviller et coll., Ann. Pharm. Franc., 24, 39 (1966).

The products of general formula (VIII) can be prepared;

• - when R is defined as above in 1) or 3), X being a nitrogen atom: by the action of a halogenated derivative of formula (Xa) or (lXb) on piperazine under the conditions described above for the reaction of products of general formula (VIII) with a benzopyran derivative of general formula (IX) in the presence of an excess of piperazine, without additional addition of an acid acceptor;
• - when R is defined as in 2): according to the method described in French patent M 2430, or according to the methods mentioned by Anwer Basha, Tet. Lett., 29 (21), 2525 (1988);
• - when R is defined as in 3), X being a nitrogen atom and W an imino radical: from a benzylpiperazine, by applying the methods mentioned by Anwer Basha, Tet. Lett., 29 (21), 2525 (1988) then the elimination of the protective radical of piperazine;
• - when R is defined as in 3), X being a carbon atom,
  • a) if W is a bond: by Friedel and Crafts reaction between an acid chloride of general formula:
    
    in which m equals 1 or 2, and a product of general formula:
    
    in which R ₂ and R ₃ are identical or different and represent hydrogen, halogen or an amino radical protected beforehand, or by application of the method described by P. Rabbe, Ber., 55, 532 (1922) ;
  • b) if W is an imino radical: by applying the method described by LD Wise et al., J. Med. Chem., 28, 606 (1985);
• - when R is defined as in 5): according to the method described by A. Quevauviller et al., Ann. Pharm. Franc., 24, 39 (1966).

dans laquelle R₁, R' et R" sont définis comme précédemment.The products of general formula (IX) can be obtained by the action of a halogenating agent or of an activated form of an alkylsulphonic or arylsulphonic acid on a derivative of 4-hydroxyalkyl benzopyran of general formula:

in which R ₁ , R 'and R "are defined as above.

When it is desired to prepare a product of general formula (IX) for which Y is a halogen atom, the halogenating agents can be chosen from thionyl chloride or halogenated phosphorus derivatives, such as oxychloride phosphorus or phosphorus tribromide. It is also possible to react allyl bromide in the presence of NN'-carbonyldümidazole.

When it is desired to prepare a product of general formula (IX) in which Y is alkylsulfonyloxy or arylsulfonyloxy, the anhydride or the halide of the corresponding acid is advantageously reacted.

The reaction is generally carried out in the presence of an organic nitrogenous base such as triethylamine or pyridine, in an organic solvent such as a chlorinated solvent (methylene chloride for example), an ether (tetrahydrofuran, dioxane for example), by operating at a temperature between 0 ° C and the reflux temperature of the reaction mixture.

The products of general formula (IX) in which R ₁ is a nitro radical can be obtained by nitration of a derivative of general formula (IX) for which R ₁ is a hydrogen atom.

Advantageously, the mixture of nitric acid and acetic acid is used at a temperature between 0 and 20 ^° C.

The products of general formula (IX) in which R ₁ is a hydroxy radical can also be obtained from a product of general formula (IX) in which R ₁ is an alkyloxy radical, by treatment in concentrated acid medium. The procedure is carried out under the conditions described above for obtaining a product of general formula (I) for which R _i represents a hydroxy radical from the corresponding product for which R _i is an alkyloxy radical.

dans laquelle R₁ , R et R" sont définis comme précédemment.The 4-hydroxyalkyl benzopyran derivative of general formula (XIV) can be prepared by reduction of the corresponding ester of general formula:

in which R ₁ , R and R "are defined as above.

One generally operates by means of aluminum hydride and lithium in an organic solvent such as an ether (tetrahydrofuran for example) at a temperature between 0 and 30 C.

dans laquelle R₁, R et R sont définis comme précédemment.The ester of general formula (XVII) can be obtained by reduction of the benzopyran derivative of general formula:

in which R ₁ , R and R are defined as above.

The process is carried out by catalytic hydrogenation in the presence of palladium, in an organic solvent such as an alcohol (methanol, ethanol for example), at a temperature between 10 and 50 ° C.

dans laquelle Ri, R" et R sont définis comme précédemment.The benzopyran derivative of general formula (XVI) can be prepared by WITTIG reaction, starting from a chromannone-4 derivative of general formula:

in which Ri, R "and R are defined as above.

The operation is advantageously carried out using ethyl diethylphosphonoacetate in the presence of sodium hydride, in an organic solvent such as an ether (tetrahydrofuran or dimethoxyethane for example) at a temperature between 0 C and the reflux temperature of the reaction mixture.

The chromannone-4 derivative of general formula (XVII) in which R _i is other than hydrogen, can be prepared by applying the method described by PFEIFFER et al., Chem. Ber., 58 (1954), or according to the methods described by GP Ellis, Heterocyclic compounds, chromenes, chromanones and chromones, John Wiley and Sons (1977).

The chromannone-4 derivative of general formula (XVII) in which R ₁ is a fluorine atom, can be prepared according to the method described in French patent application 2,588,860.

The chromannone-4 derivatives of general formula (XVII) in which R ₁ is an amino, alkylsulfonamido or acylamino radical, can be obtained from the chromannone-4 derivative of general formula (XVII) for which R ₁ is a nitro radical, by analogy with the methods described for the preparation of the products of general formula (I) for which the radical R ₁ is defined as above.

Dimethyl-2,2 chromannone-4 can be obtained according to the method described in Belgian patent 844,943.

• - lorsque W est une liaison, par réaction de Friedel et Crafts entre un chlorure d'acide de formule générale : Hal(CH₂)_mCOCI (XVIII) dans laquelle m est égale à 0 ou 1 et un produit de formule générale (XIII), ou
• - lorsque W est un radical imino, selon la méthode décrite par L.D. Wise et coll., J. Med. Chem., 28, 606 (1985).

Products of general formula (Xb) can be prepared

• - when W is a bond, by Friedel and Crafts reaction between an acid chloride of general formula: Hal (CH ₂ ) _m COCI (XVIII) in which m is equal to 0 or 1 and a product of general formula (XIII ), or
• - when W is an imino radical, according to the method described by LD Wise et al., J. Med. Chem., 28, 606 (1985).

The benzopyran derivatives of general formula (XI) can be obtained by the action of piperazine on a benzopyran derivative of general formula (IX).

The reaction is carried out under the conditions described above for the reaction of the products of general formula (VIII) with the benzopyran derivatives of general formula (IX), in the presence of an excess of piperazine (2 equivalents), without additional addition of 'an acid acceptor.

The enantiomers of the products according to the invention can be separated according to known methods.

One operates in particular by preparation of the enantiomer of the hydroxyethylbenzopyran derivative of general formula (XIV) which is transformed into product of general formula (I) according to the process described above.

dans laquelle R₁ , R et R sont définis comme précédemment, séparation des isomères par chromatographie, hydrolyse de l'isomère recherché puis réduction de l'acide obtenu.The optically active derivative of general formula (XIV) is obtained by preparation of an optically active amide of general formula:

in which R ₁ , R and R are defined as above, separation of the isomers by chromatography, hydrolysis of the desired isomer then reduction of the acid obtained.

The hydrolysis of the isomer of the product of general formula (XIX) can be carried out by any known method which does not alter the rest of the molecule; it is advantageously carried out in an acid medium (acetic acid, hydrochloric acid in mixtures) at the reflux temperature of the reaction mixture.

The reduction of the acid to alcohol is carried out according to the usual methods. In particular, diborane is used as reducing agent and it is advantageously carried out in an ether such as tetrahydrofuran at temperatures between 0 and 30 ^° C.

dans laquelle R₁, R et R sont définis comme précédemment, par toute méthode connue pour préparer un amide à partir d'un acide.The product of general formula (XIX) can be prepared from the acid of general formula:

in which R ₁ , R and R are defined as above, by any known method for preparing an amide from an acid.

The operation is advantageously carried out by means of the acid chloride of general formula (XX) (which can be prepared in situ) in an inert organic solvent such as a chlorinated solvent (dichloromethane for example) in the presence of an acceptor agent. acid as an organic nitrogenous base (triethylamine for example), at a temperature between 0 and 30 ^° C.

The acid of general formula (XX) can be obtained from the corresponding ester, by any known method for obtaining an acid from an ester without affecting the rest of the molecule.

The saponification of the ester of general formula (XIV) is carried out in particular with potassium hydroxide, in methanol at the reflux temperature of the reaction mixture.

The acid chloride is prepared by treatment of the corresponding acid with thionyl chloride at the reflux temperature of the reaction mixture.

The new benzopyran derivatives according to the invention can be purified if necessary, by physical methods such as crystallization or chromatography.

The products according to the invention can be converted into addition salts with acids. The salt formed precipitates after optional concentration of its solution, it is separated by filtration, decantation or lyophilization. According to the process of the present invention, the products are generally obtained in the form of oxalate. These salts can be released and transformed into salts of other acids according to the usual methods.

As examples of pharmaceutically acceptable salts, mention may be made of addition salts with mineral (hydrochlorides, hydrobromides, sulfates, nitrates, phosphates) or organic (succinates, fumarates, acetates, propionates, maleates, methanesulfonates, p.toluenesulfonates, isethionates) acids. tes) or substitution derivatives of these compounds.

The products according to the invention show antiarrhythmic properties. In particular their particularly interesting anti-fibrillating properties, characteristic of class III of VAUGHAN WILLIAMS, result in an extension of the refractory periods.

They cause, in vitro on the guinea pig papillary muscle, an increase of between 5% and values greater than 30%, of the duration of the initial action potential, according to the technique of measurements of recording of the intracellular action potential described by E. CORABOEUF and S. WEIDMANN, CR Soc. Biol., 143, 1329 (1949).

Furthermore, the benzopyran derivatives according to the invention show low toxicity. They were generally shown to be non-toxic at 300 mg / kg orally in mice.

• RI, R et R sont des atomes d'hydrogène, et R représente un radical tel que défini en 1) pour lequel R₂ et R₃ sont des atomes d'hydrogène, ou
• R représente un radical tel que défini en 2) pour lequel n égale 0, R₄ est un atome d'hydrogène, un radical alcoyle ou un radical de structure (IVa) dans laquelle Rs est Rs sont des atomes d'hydrogène ou d'halogène, ou des radicaux alcoyloxy et Q représente un radical acétyle, méthylsulfonyle ou un radical de formule générale (IVb) dans laquelle Y est un radical carbonyle ou sulfonyle et Z est une liaison ou un radical méthylène ou imino, et R₂ et R₃ sont des atomes d'hydrogène ou d'halogène ou des radicaux alcoyle ou méthylsulfonamido, ou
• R représente un radical tel que défini en 3) pour lequel n égale 0, m égale 0 à 2, W est une liaison ou un radical imino, Ar est pyridyle, indolyle ou phényle éventuellement substitué par un atome d'halogène, ou des radicaux alcoyle ou alcoyloxy et X est un atome de carbone ou d'azote, ou R représente un radical tel que défini en 4) pour lequel R₇ représente un atome d'hydrogène.

Of particular interest are the products of general formula (I) for which,

• RI, R and R are hydrogen atoms, and R represents a radical as defined in 1) for which R ₂ and R ₃ are hydrogen atoms, or
• R represents a radical as defined in 2) for which n equals 0, R ₄ is a hydrogen atom, an alkyl radical or a radical of structure (IVa) in which Rs is Rs are hydrogen atoms or halogen, or alkyloxy radicals and Q represents an acetyl, methylsulfonyl radical or a radical of general formula (IVb) in which Y is a carbonyl or sulfonyl radical and Z is a bond or a methylene or imino radical, and R ₂ and R ₃ are hydrogen or halogen atoms or alkyl or methylsulfonamido radicals, or
• R represents a radical as defined in 3) for which n equals 0, m equals 0 to 2, W is a bond or an imino radical, Ar is pyridyl, indolyl or phenyl optionally substituted by a halogen atom, or radicals alkyl or alkyloxy and X is a carbon or nitrogen atom, or R represents a radical as defined in 4) for which R ₇ represents a hydrogen atom.

• - N-{[dihydro-3,4 2H-benzopyran-1 yl-4)-2 éthyl]-1 pipéridyl-4} acétanilide et ses sels ;
• - [(dihydro-3,4 2H-benzopyran-1 yl-4)-2 éthyl]-1 nicotinoyl-4 pipérazine et ses sels ;
• - N-{[dihydro-3,4 2H-benzopyran-1 yl-4)-2 éthyl}-1 pipéridyl-4} N-phényl fluoro-4 benzamide et ses sels ;
• - benzoyl-4 [(dihydro-3,4 2H-benzopyran-1 yl-4)-2 éthyl]-1 pipéridine et ses sels ;
• - {[dihydro-3,4 2H-benzopyran-1 yl-4)-2 éthyl]-1 pipéridyl-4} phényl méthanoxime et ses sels ;

And among these more especially active products are the products of general formula (I) given below

• - N - {[3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} acetanilide and its salts;
• - [(3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl] -1 nicotinoyl-4 piperazine and its salts;
• - N - {[3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl} -1 piperidyl-4} N-phenyl fluoro-4 benzamide and its salts;
• - benzoyl-4 [(3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl] -1 piperidine and its salts;
• - {[3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} phenyl methanoxime and its salts;

The following examples, given without limitation, illustrate the present invention.

In the examples which follow, unless otherwise stated, the chromatographies are carried out on silica gel (60-200 u.).

EXAMPLE 1

Is refluxed for 6 hours, 1.56 g of (2-bromo-ethyl) -4-3,4-dihydro-2H-benzopyran, 2 g of N- (piperidyl-4)-3,4-dimethoxy-acetanilide, 1.6 g of dry potassium carbonate and 1.07 g of potassium iodide in 50 cm ³ of butanone-2.

The reaction mixture is filtered on sintered glass and then after evaporation of the solvent under reduced pressure (5.2 kPa), the oil obtained is taken up in 10 cm3 of a solution (5N) of potassium carbonate and 40 cm3 of water added then extracted with twice 75 cm3 of ethyl acetate.

The organic phase is then dried over magnesium sulfate and then concentrated to dryness under reduced pressure.

The evaporation residue is chromatographed on a 2.8 cm diameter column containing 25 g of silica gel, eluting with 210 cm ³ of a dichloromethane - isopropanol mixture (90-10 by volume) and collecting fractions of 30 cm ^3. The fractions between 60 and 210 cm ³ are concentrated to dryness.

The oil obtained is taken up in the minimum amount of acetone and 0.39 g of oxalic acid dissolved in acetone is added, then it is concentrated to dryness and crystallized from butanone-2.

1.6 g of N - {[(3,4-dihydro-3,4H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} dimethoxy-3,4-acetanilide in the form of 1.6 g of oxalate of N - {[(dihydro-3,4 2H-benzopyran-1 yl-4) -2 '' a white solid melting at 174 ° C.

N- (piperidyl-4) dimethoxy-3,4 acetanilide can be prepared by applying the method described in French patent M 2430, but starting from 8.4 g of N- (benzyl-1 piperidyl-4) dimethoxy -3.4 acetanilide, 0.85 g of palladium on carbon (5%) in 100 cm3 of an acetic acid - water mixture (70-30 by volume) and carrying out the hydrogenation at 60 C.

6.3 g of N- (piperidyl-4) dimethoxy-3,4 acetanilide are thus obtained in the form of a whitish powder melting at 210 ° C.

The N- (benzyl-1 piperidyl-4) dimethoxy-3,4 acetanilide can be prepared according to the method described in French patent M 2430, but starting from 10 g of N-benzyl (dimethoxy-3,4 anilino) - 4 piperidine, 20 cm3 of acetic anhydride in 30 cm3 of acetic acid.

10.9 g of N- (1-benzyl-4-piperidyl)-3,4-dimethoxy acetanilide are thus obtained in the form of a whitish solid melting at 117 C.

N-benzyl (3,4-dimethoxy anilino) -4 piperidine can be prepared according to the method described in French patent M 2430, but from 37.8 g of N-benzylpiperidone, 19.2 g of dimethoxy- 3.4 aniline in 200 cm3 of toluene supplemented with 0.017 g of paratoluenesulfonic acid and 1.4 g of lithium aluminum hydride in 200 cm3 of ethyl ether.

15 g of N-benzyl (3,4-dimethoxy anilino) -4 piperidine are thus obtained in the form of a whitish solid melting at 66 ° C.

• A 115 cm³ d'acétonitrile on ajoute, sous agitation, 13,8 g de (dihydro-3,4 2H-benzopyran-1 yl-4)-2 éthanol, puis 91,2 g de bromure d'allyle et enfin 12,6 g de NN'-carbonyldiimidazole.

2-bromo-4-ethyl-3,4-dihydro-2H-benzopyran can be prepared as follows:

• To 115 cm ³ of acetonitrile, 13.8 g of (3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethanol are added, with stirring, then 91.2 g of allyl bromide and finally 12 , 6 g of NN'-carbonyldiimidazole.

The mixture is stirred for 3 hours 10 minutes at approximately 20 ° C. and then 2 hours at reflux.

The reaction mixture is then concentrated under reduced pressure (5.2 kPa) and the residue obtained is chromatographed on a column 5.5 cm in diameter containing 200 g of silica gel, eluting with 550 cm ³ of dichloromethane and collecting fractions of 100 cm ³ . The fractions between 350 and 550 cm ³ are concentrated to dryness.

17.7 g of (2-bromo-ethyl) -4 dihydro-3,4 2H-benzopyran are thus obtained in the form of a light brown oil.

• 6,8 à 7,2 (mt, 4H aromatiques)
• 4,21 (mt, -O-CH₂-)
• 3,55 (mt, -CH₂-Br)
• 3,08 (mt,
  
  -CH-)
• 1,92 et 2,92 (mt, -CH₂-en-3)
• 2,08 et 2,34 (mt, -CH₂CH₂Br)

Proton NMR spectrum (250 MHz, CDCl ₃ , δ in ppm):

• 6.8 to 7.2 (mt, 4H aromatic)
• 4.21 (mt, -O-CH ₂ -)
• 3.55 (mt, -CH ₂ -Br)
• 3.08 (mt,
  
  -CH-)
• 1.92 and 2.92 (mt, -CH ₂ -in-3)
• 2.08 and 2.34 (mt, -CH ₂ CH ₂ Br)

• A 5,96 g d'hydrure de lithium et d'aluminium, on ajoute 500 cm³ de tétrahydrofuranne et refroidit à 0°C. On ajoute alors, sous agitation, 17,25 g de (dihydro-3,4 2H-benzopyran-1 yl-4)-2 éthanoate d'éthyle dans 60 cm³ de tétrahydrofuranne.

The (dihydro-3,4 2H-benzopyran-1 yl-4) -2 ethanol can be prepared as follows:

• To 5.96 g of lithium aluminum hydride, 500 cm ³ of tetrahydrofuran are added and the mixture is cooled to 0 ° C. 17.25 g of (dihydro-3,4 2H-benzopyran-1 yl-4) -2 ethyl ethanoate in 60 cm ³ of tetrahydrofuran are then added, with stirring.

After stirring for 1 hour at 20 ° C., it is hydrolyzed with stirring by addition of hydrated sodium sulfate (10 H ₂ 0) until precipitation and then the reaction mixture is left to stand for hours.

After filtration of the precipitate formed and evaporation of the solvent under reduced pressure, 13.8 g of (dihydro-3,4 2H-benzopyran-1 yl-4) -2 ethanol are isolated in the form of a brown oil.

• 6,8 à 7,2 (mt, 4H aromatiques)
• 4,22 (mt, -O-CH₂-)
• 3,83 (mt, -CH₂-OH)
• 3,04 (mt,
  
  CH-)
• 1,83 et 2,90 (mt, -CH_z- en -3 et -CH₂-CH₂OH)
• 1,62 (s, -OH)

NMR spectrum (250 MHz, CDCI ₃ , δ in ppm):

• 6.8 to 7.2 (mt, 4H aromatic)
• 4.22 (mt, -O-CH ₂ -)
• 3.83 (mt, -CH ₂ -OH)
• 3.04 (mt,
  
  CH-)
• 1.83 and 2.90 (mt, -CH _z - in -3 and -CH ₂ -CH ₂ OH)
• 1.62 (s, -OH)

Ethyl (3,4-dihydro-2H-benzopyran-1 yl-4) ethanoate can be prepared as follows: 50.6 g of (3,4-dihydro-2H-benzopyran-1 ylidene-4) acetate ethyl (E, Z) in 1 liter of methanol, are hydrogenated at 20 ⁰ C at atmospheric pressure, in the presence of 5.06 g of palladium on charcoal (10%).

After filtration on KIESELGUHR and concentration to dryness under reduced pressure (5.2 kPa), 48.8 g of ethyl (3,4-dihydro-2H-benzopyran-1 yl-4) ethanoate are obtained in the form of an oil. pale yellow.

• 6,75 à 7,2 (mt, 4H aromatiques)
• 4,98 (q + mt, -0-CH₂- + -CO-OCH₂-CH₃)
• 3,37 (mt, -CH-)
• 2,53 et 2,82 (dd, -CH₂-CO-)
• 1,87 et 2,18 (mt, -CH₂- en -3)
• 1,30 (t, -COO-CH₂-CH₃)

NMR spectrum (250 MHz, CDCl ₃ , δ in ppm):

• 6.75 to 7.2 (mt, 4H aromatic)
• 4.98 (q + mt, -0-CH ₂ - + -CO-OCH ₂ -CH ₃ )
• 3.37 (mt, -CH-)
• 2.53 and 2.82 (dd, -CH ₂ -CO-)
• 1.87 and 2.18 (mt, -CH ₂ - in -3)
• 1.30 (t, -COO-CH ₂ -CH ₃ )

• A 1 litre de tétrahydrofuranne anhydre, on ajoute, sous agitation, 20,4 g d'hydrure de sodium (80 %) puis par petites portions 153 g de diéthylphosphonoacétate d'éthyle tout en maintenant la température du mélange réactionnel aux environs de 20° C. Puis la solution jaune claire ainsi obtenue est additionnée de 45 g de chromannone-4 dans 100 cm³ de tétrahydrofuranne anhydre en maintenant la température en dessous de 0°C. Après 22 heures à 20 C, on concentre sous pression réduite le mélange réactionnel puis extrait

l'huile obtenue par 2 fois 700 cm³ de dichlorométhane. La phase organique est lavée à l'eau puis séchée sur sulfate de magnésium et concentrée à sec sous pression réduite. Le résidu d'évaporation est chromatographié sur une colonne de 9 cm de diamètre, contenant 1,6 kg de gel de silice, en éluant par 6,3 litres d'un mélange cyclohexane - acétate d'éthyle (90-10 en volumes) et en recueillant des fractions de 250 cm^3. Les fractions comprises entre 2,8 et 6,3 litres sont concentrées à sec.(3,4-dihydro-2H-benzopyran-1-ylidene-4) ethyl acetate (E, Z) can be prepared in the following manner:

• To 1 liter of anhydrous tetrahydrofuran, 20.4 g of sodium hydride (80%) are added, with stirring, then in small portions 153 g of ethyl diethylphosphonoacetate while maintaining the temperature of the reaction mixture around 20 °. C. Then the light yellow solution thus obtained is added with 45 g of chromannone-4 in 100 cm ³ of anhydrous tetrahydrofuran while maintaining the temperature below 0 ° C. After 22 hours at 20 ° C., the reaction mixture is concentrated under reduced pressure and then extracted.

the oil obtained with 2 times 700 cm ³ of dichloromethane. The organic phase is washed with water and then dried over magnesium sulfate and concentrated to dryness under reduced pressure. The evaporation residue is chromatographed on a column 9 cm in diameter, containing 1.6 kg of silica gel, eluting with 6.3 liters of a cyclohexane - ethyl acetate mixture (90-10 by volume) and collecting 250 cm ³ fractions ^. The fractions between 2.8 and 6.3 liters are concentrated to dryness.

50.6 g of a mixture of E and Z isomers of (3,4-dihydro-2H-benzopyran-1-ylidene-4) ethyl acetate are thus obtained in the form of a pale yellow oil.

• Isomère E (75 %) :
• 6,8 à 7,61 (mt, 4H aromatiques)
• 6,36 (s, = CH-CO-)
• 4,23 (mt, -O-CH₂-)
• 4,23 (mt, -CO-OCH₂-CH₃)
• 3,41 (mt, -CH₂- en -3)
• 1,32 (mt, -CO-OCH₂-CH₃)
• Isomère Z (25 %) :
• 6,8 à 7,83 (mt, 4H aromatiques)
• 5,61 (s, = CH-CO-)
• 4,38 (t, -O-CH₂-)
• 4,23 (mt, -CO-OCH₂-CH₃)
• 2,65 (t, -CH₂- en -3)
• 1,32 (mt, -CO-OCH₂-CH₃)

NMR spectrum (400 MHz, CDCl ₃ , 5 in ppm):

• Isomer E (75%):
• 6.8 to 7.61 (mt, 4H aromatic)
• 6.36 (s, = CH-CO-)
• 4.23 (mt, -O-CH ₂ -)
• 4.23 (mt, -CO-OCH ₂ -CH ₃ )
• 3.41 (mt, -CH ₂ - in -3)
• 1.32 (mt, -CO-OCH ₂ -CH ₃ )
• Isomer Z (25%):
• 6.8 to 7.83 (mt, 4H aromatic)
• 5.61 (s, = CH-CO-)
• 4.38 (t, -O-CH ₂ -)
• 4.23 (mt, -CO-OCH ₂ -CH ₃ )
• 2.65 (t, -CH ₂ - in -3)
• 1.32 (mt, -CO-OCH ₂ -CH ₃ )

EXAMPLE 2

The procedure is as in Example 1, but starting with 2 g of (2-bromo-ethyl) -4-3,4-dihydro-2H-benzopyran, 2 g of N- (piperidyl-4) acetanilide, 2 g of dry potassium carbonate and 1.38 g of potassium iodide in 50 cm3 of butanone-2.

The oil obtained is taken up in 10 cm3 of a solution (5N) of potassium carbonate and added 100 cm3 of water and then extracted with twice 75 cm3 of ethyl ether. The combined organic phases are then dried over magnesium sulfate and then concentrated to dryness under reduced pressure (5.2 kPa).

The oil obtained is chromatographed on a 2.8 cm diameter column containing 25 g of silica gel, eluting with a dichloromethane - isopropanol mixture (90-10 by volume) and collecting 30 cm ³ fractions. The fractions between 60 and 240 cm3 are concentrated to dryness.

The oil obtained is dissolved in the minimum of acetone at 40 ^. C and add a solution of 0.71 g of oxalic acid in 10 cm3 of acetone.

3.05 g of N - {[(3,4-dihydro-3,4H 2-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} acetanilide acid oxalate are thus obtained in the form of a white melting solid at 183 "C.

N- (piperidyl-4) acetanilide can be prepared according to the method described in French patent M 2430.

EXAMPLE 3

Heated at reflux for 18 hours, 1.47 g of (2-bromo-ethyl) -4-3,4-dihydro-2H-benzopyran, 1.83 g of (3,4-dimethoxyphenyl) -1 hydrochloride (piperidyl -4) -3 propanone-1, 1.51 g of dry potassium carbonate and 1 g of potassium iodide in 50 cm3 of butanone-2.

The reaction mixture is filtered on sintered glass and then, after evaporation of the solvent under reduced pressure (5.2 kPa), the reaction mixture is taken up in 20 cm3 of distilled water and extracted with three times 70 cm3 of ethyl acetate. The organic phase is then dried over magnesium sulfate and then concentrated to dryness under reduced pressure (5.2 kPa).

The residue obtained is purified by chromatography on a column 5.5 cm in diameter containing 200 g of silica gel (32-63 µ), eluting with 1.6 liters of a dichloromethane-ethanol mixture (95-5 by volume ) and then 4.4 liters of a dichloromethane - ethanol mixture (90-10 by volume) and collecting fractions of 200 cm3. The fractions between 2.6 and 4.4 liters are concentrated to dryness.

The product obtained is dissolved in the minimum of acetone at 40 ° C. and a solution of 0.6 g of oxalic acid in acetone is added. The white precipitate formed is filtered on sintered glass and is then recrystallized a first time from 250 cm3 of ethanol and a second time from 100 cm3 of a mixture ethanol and butanone-2 (75-25 by volume).

This gives 2.65 g of acid oxalate of {[(3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} -3 (3,4-dimethoxyphenyl) - 1 propanone in the form of a white solid, melting at 175 ° C.

• A une solution de 140 cm3 de diméthoxy-1,2 benzène dans 200 cm3 de dichlorométhane et de 75 g de chlorure de l'acide benzoyl-1 pipéridyl-4 propionique est ajouté, peu à peu, par fractions de 5-6 g, 47 g de chlorure d'aluminium.

(3,4-dimethoxyphenyl) -1 (piperidyl-4) -3 propanone-1 can be prepared as follows:

• To a solution of 140 cm3 of 1,2-dimethoxy benzene in 200 cm3 of dichloromethane and of 75 g of chloride of 1-benzoyl-4-piperidyl propionic acid is added little by little in fractions of 5-6 g, 47 g of aluminum chloride.

Then heated 9 hours to boiling and then the reaction mixture is left overnight at room temperature. The reaction mixture is then poured into ice and after decantation and washing with distilled water, the organic phase is concentrated to dryness.

The oil obtained is taken up in 200 cm3 of a 3N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is separated and then, after washing with distilled water, it is concentrated to dryness and the oil obtained is brought to reflux for 48 hours in 1.2 liters of a 3.25N hydrochloric acid solution.

After cooling, the benzoic acid crystals are filtered and the filtrate is made alkaline with a concentrated sodium hydroxide solution. After three extractions with dichloromethane, the organic phase is washed with water and then dried over magnesium sulfate. Concentration to dryness and the oil obtained is taken up in a 4N solution of hydrochloric acid in ethanol.

8.49 g of (3,4-dimethoxyphenyl) -1 (piperidyl-4) -3 propanone hydrochloride are thus obtained in the form of white crystals, melting at 193 ° C.

• On chauffe à reflux, pendant 2 heures, 75,4 g d'acide benzoyl-1 pipéridyl-4 propionique avec 84 cm3 de chlorure de thionyle dans 400 cm3 de chloroforme. Après concentration à sec sous pression réduite, on obtient 75 g du chlorure de l'acide benzoyl-1 pipéridyl-4 propionique sous forme d'un solide brun qui est utilisé tel quel pour l'étape suivante.

Benzoyl-1 piperidyl-4-propionic acid chloride can be prepared as follows:

• 75.4 g of 1-benzoyl-4-piperidyl-propionic acid with 84 cm3 of thionyl chloride in 400 cm3 of chloroform are heated to reflux for 2 hours. After concentration to dryness under reduced pressure, 75 g of the chloride of 1-benzoyl-piperidyl-4-propionic acid are obtained in the form of a brown solid which is used as it is for the following stage.

Benzoyl-1 piperidyl-4 propionic acid can be prepared according to the methods described in Beil., 22 - (III / IV), 161 and by C.F. Koelschr, J. Am. Chem. Soc., 65, 2460 (1943).

EXAMPLE 4

The procedure is as in Example 3, but starting from 1.60 g of (2-bromo-ethyl) -4-3,4-dihydro-2H-benzopyran, 2.30 g of N- (4-fluoro-phenyl) hydrochloride N-piperidyl-4 fluoro-4 benzamide, 1.80 g of dry potassium carbonate and 0.80 g of potassium iodide in 50 cm ³ of butanone-2.

After 18 hours of reflux, the reaction mixture is filtered on sintered glass and then after evaporation of the solvent under reduced pressure (5.2 kPa) the yellow oil obtained is taken up in 100 cm ³ of dichlomethane and washed with a 20% ammoniacal solution . After washing with water, the organic phase is then dried over magnesium sulfate and then concentrated to dryness under reduced pressure (5.2 kPa). The yellow oil obtained is purified by chromatography on a column 5.5 cm in diameter containing 100 g of silica gel (63-200 µ), eluting with 810 cm ³ of a dichloromethane-ethanol mixture (95-5 by volume ) and collecting 30 cm ³ fractions ^. fractions between 200 and 810 cm ³ are concentrated to dryness.

The yellow oil obtained is taken up in the minimum amount of acetone and 0.90 g of oxalic acid dissolved in acetone is added. The white precipitate formed is filtered through sintered glass and is then recrystallized from 50 cm ³ of ethanol.

2 g of N - {[dihydro-3,4 2H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} N- (4-fluoro-phenyl) 4-fluoro-benzamide are thus obtained. in the form of a white powder melting at 150 ° C.

• 3,2 g de chlorhydrate de N-(benzyl-1 pipéridyl-4) N-(fluoro-4 phényl) fluoro-4 benzamide dans 50 cm³ d'éthanol à 95 % sont hydrogénés à 60 C, sous pression atmosphérique en présence de 0,5 g d'hydroxyde de palladium. Après filtration sur Kieselguhr et concentration à sec sous pression réduite (5,2 kPa) on obtient 2,3 g de chlorhydrate de N-(fluoro-4 phényl) N-(pipéridyl-4) fluoro-4 benzamide sous forme d'une poudre blanche fondant à 170° C.

N- (4-fluoro-phenyl) N-piperidyl-4-fluoro-4-benzamide hydrochloride can be prepared in the following manner:

• 3.2 g of N- (1-benzyl-4-piperidyl-4) hydrochloride N- (4-fluoro-phenyl) 4-fluoro benzamide in 50 cm ³ of 95% ethanol are hydrogenated at 60 ° C. under atmospheric pressure in the presence 0.5 g of palladium hydroxide. After filtration through Kieselguhr and concentration to dryness under reduced pressure (5.2 kPa), 2.3 g of N- (4-fluoro-phenyl) N- (piperidyl-4) fluoro-4-benzamide hydrochloride are obtained in the form of a white powder melting at 170 ° C.

• 2,8 g de N-benzyl (fluoro-4 anilino)-4 pipéridine dissous dans 30 cm³ de trichlorométhane sont agités pendant 18 heures avec 2 cm³ du chlorure de l'acide fluoro-4 benzoïque et en présence de 5 cm³ de triéthylamine. Le mélange réactionnel est ensuite lavé à deux reprises par 30 cm³ d'une solution (3N) de soude puis par 30 cm³ d'eau. La phase organique est alors séchée sur sulfate de magnésium puis

concentrée sous pression résuite (5,2 kPa). Par addition de 5 cm³ d'une solution 3,4 N d'acide chlorhydrique dans l'isopropanol et recristallisation dans 100 cm³ d'un mélange acétone-éthanol (50-50 en volumes), on obtient 3,2 g de chlorhydrate de N-(benzyl-1 pipéridyl-4) N-(fluoro-4 phényl) fluoro-4 benzamide sous forme d'une poudre blanche fondant à 210 C.The N- (1-benzyl-piperidyl-4) N- (4-fluoro-phenyl) 4-fluoro-benzamide hydrochloride can be prepared in the following manner:

• 2.8 g of N-benzyl (4-fluoro anilino) -4 piperidine dissolved in 30 cm ³ of trichloromethane are stirred for 18 hours with 2 cm ³ of 4-fluoro benzoic acid chloride and in the presence of 5 cm ³ triethylamine. The reaction mixture is then washed twice with 30 cm ³ of a solution (3N) of sodium hydroxide and then with 30 cm ³ of water. The organic phase is then dried over magnesium sulfate and then

concentrated under reduced pressure (5.2 kPa). By adding 5 cm ³ of a 3.4 N solution of hydrochloric acid in isopropanol and recrystallization from 100 cm ³ of an acetone-ethanol mixture (50-50 by volume), 3.2 g of N- (1-benzyl-piperidyl-4) N- (4-fluoro-phenyl) fluoro-4-benzamide hydrochloride in the form of a white powder melting at 210 C.

• 2 g de benzylpipéridone en solution dans 10 cm³ de toluène sont agités sous argon pendant 48 heures à température ambiante en présence de 1,4 g de fluoro-4 aniline et de 4 g de tamis moléculaire 5 Â, Après filtration et concentration à sec sous pression réduite (5,2 kPa) on obtient des cristaux jaunes qui sont alors dissous dans 30 cm³ de méthanol. Cette solution est ensuite ajoutée à une solution refroidie à 0-5 ° C, de 1,34 g de cyanoborohydrure de sodium et de 1,4 g de chlorure de zinc dans 20 cm³ de méthanol. Après 20 heures à température ambiante, on reprend par 5 cm³ d'une solution 10N de soude et par 20 cm³ d'eau et chauffe à reflux pendant 1 heure. On filtre sur fritté et le filtrat est extrait à deux reprises par 100 cm³ de dichlorométhane. La phase organique est ensuite séchée sur sulfate de magnésium puis concentrée à sec sous pression réduite (5,2 kPa). On obtient ainsi 2,8 g de N-benzyl (fluoro-4 anilino)-4 pipéridine sous forme d'une poudre blanchâtre fondant à 84 C.

N-Benzyl (4-fluoro anilino) -4 piperidine can be prepared as follows:

• 2 g of benzylpiperidone in solution in 10 cm ³ of toluene are stirred under argon for 48 hours at room temperature in the presence of 1.4 g of 4-fluoroaniline and 4 g of 5 A molecular sieve, After filtration and concentration to dryness under reduced pressure (5.2 kPa), yellow crystals are obtained which are then dissolved in 30 cm ³ of methanol. This solution is then added to a solution cooled to 0-5 ° C, 1.34 g of sodium cyanoborohydride and 1.4 g of zinc chloride in 20 cm ³ of methanol. After 20 hours at room temperature, the residue is taken up in 5 cm ³ of a 10N sodium hydroxide solution and in 20 cm ³ of water and heated to reflux for 1 hour. Filtered on a frit and the filtrate is extracted twice with 100 cm ³ of dichloromethane. The organic phase is then dried over magnesium sulfate and then concentrated to dryness under reduced pressure (5.2 kPa). 2.8 g of N-benzyl (4-fluoro anilino) -4 piperidine are thus obtained in the form of a whitish powder melting at 84 C.

EXAMPLE 5

The procedure is as in Example 4, but starting with 1.6 g of (2-bromo-ethyl) -4-3,4-dihydro-2H-benzopyran, 2.21 g of N-phenyl N- hydrochloride (piperidyl- 4) 4-fluoro benzamide, 1.8 g of dry potassium carbonate and 0.8 g of potassium iodide in 50 cm ³ of butanone-2. The oil obtained is taken up in the minimum amount of acetone and 0.6 g of oxalic acid dissolved in acetone is added. The white precipitate formed is filtered through sintered glass and then recrystallized from 50 cm ³ of ethanol. 2.7 g of acid oxalate of N - {[3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} N-phenyl fluoro-4 benzamide in the form of d are thus obtained. '' a white solid melting at 161 C.

The N _- phenyl N- (piperidyl) fluoro-4 benzamide hydrochloride is prepared as described in Example 4 for N- (4-fluoro phenyl) N- (piperidyl-4) fluoro-4 benzamide.

EXAMPLE 6

The procedure is as in Example 4, but starting with 1.6 g of (2-bromo-ethyl) -4-3,4-dihydro-2H-benzopyran, 2.1 g of N-phenyl N- hydrochloride (piperidyl- 4) benzamide, 1.8 g of dry potassium carbonate and 0.8 g of potassium iodide in 50 cm ³ of butanone-2. The oil obtained is taken up in the minimum amount of acetone and 0.6 g of oxalic acid dissolved in acetone is added. The white precipitate formed is filtered through sintered glass and then recrystallized from 45 cm ³ of ethanol.

2.7 g of acid oxalate of N - {[3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} N-phenyl benzamide are thus obtained in the form of a solid. white melting at 135 ° C.

The N-phenyl N- (piperidyl-4) benzamide hydrochloride is prepared as described in Example 4 for N- (4-fluoro phenyl) N- (piperidyl-4) fluoro-4 benzamide.

EXAMPLE 7

The procedure is as in Example 1, but starting with 2.5 g of (2-bromo-ethyl) -4-3,4-dihydro-2H-benzopyran, 3.26 g of N- (2,6-dimethylphenyl ) N- (piperidyl-4) fluoro-4 benzamide, 2.76 g of dry potassium carbonate and 1.66 g of potassium iodide in 25 cm ³ of butanone-2 while heating for 3 hours.

The butanone-2 is evaporated under reduced pressure (5.2 kPa) the residue is taken up in 50 cm ³ of water and extracted with 100 cm ³ and then twice 50 cm ³ of dichloromethane. The combined organic phases are dried over magnesium sulfate and then concentrated to dryness under reduced pressure (5.2 kPa). The oil obtained is chromatographed on a column 4 cm in diameter containing 150 g of silica gel, eluting with a dichloromethane-ethanol mixture (98-2 by volume) and collecting 25 cm ³ fractions ^. The fractions included between 125 and 1100 cm ³ are concentrated to dryness. The oil obtained is dissolved in 45 cm ³ of absolute ethanol and added with 0.83 g of hot oxalic acid. It is left to crystallize at + 5 C.

This gives 3.75 g of acid oxalate of N - {[3,4-dihydro-3,4H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} N- (2,6-dimethylphenyl) 4-fluoro benzamide, in the form of a white solid melting at 205 C.

The N- (2,6-dimethylphenyl) N-piperidyl-4 fluoro-4 benzamide can be prepared as follows:

A solution of 8.57 g of N- (benzyl-1 piperidyl-4) N- (2,6-dimethylphenyl) fluoro-4 benzamide in 100 cm ³ of ethanol is added with 2 cm ³ of an aqueous solution 12N hydrochloric acid and 1 g of 10% palladium on carbon. This suspension is subjected to the action of hydrogen under atmospheric pressure at 55. C. After 4 hours, the theoretical volume has been absorbed. The catalyst is cooled and filtered, which is washed three times with 20 cm ³ of ethanol.

The ethanol is evaporated under reduced pressure (5.2 kPa). The solid obtained is taken up in 50 cm ³ of water, added with 2.5 cm ³ of 10N sodium hydroxide and extracted 7 times with 50 cm ³ of dichloromethane. The combined organic phases are concentrated to dryness under reduced pressure (5.2 kPa).

6.6 g of N- (2,6-dimethylphenyl) N- (piperidyl-4) fluoro-4 benzamide are obtained in the form of a brown oil.

• - 6,65 à 7,3 (Mt, 7H aromatiques)
• - 4,1 (Mt, 1 H,
  
  N-CH
  
  de la pipéridine)
• - 3,06 (D large, J = 12,5, 2H équatoriaux des N-CH₂- de la pipéridine)
• - 2,65 (T large, J = 12,5 + S, 3H axiaux des N-CH₂- de la pipéridine + -NH-)
• - 2,17 (S, 6H : Ar-CH3)
• - 1,88 (D large, J = 12,5, 2H : H équatoriaux des -CH₂- de la pipéridine)
• - 1,66 (Mt, 2H, H axiaux des -CH₂- de la pipéridine).

NMR spectrum (300 MHz, CDCl ₃ , δ in ppm, J in Hz)

• - 6.65 to 7.3 (Mt, 7H aromatic)
• - 4.1 (Mt, 1 H,
  
  N-CH
  
  piperidine)
• - 3.06 (D wide, J = 12.5, 2H equatorial of N-CH ₂ - of piperidine)
• - 2.65 (broad T, J = 12.5 + S, 3H axial of N-CH ₂ - piperidine + -NH-)
• - 2.17 (S, 6H: Ar-CH3)
• - 1.88 (D wide, J = 12.5, 2H: H equatorials of -CH ₂ - of piperidine)
• - 1.66 (Mt, 2H, axial H of -CH ₂ - of piperidine).

• A une solution de 6,5g de N-(diméthyl-2,6 phényl) (benzyl-1 pipéridyl-4) amine dans 100 cm³ de trichlorométhane, on additionne 4,5 cm³ de triéthylamine puis 3,1 cm³ de chlorure de l'acide fluoro-4 benzoïque, en maintenant à +25°C. Après 30 minutes, on verse 100 cm³ d'eau, puis après 16 heures, on décante et réextrait la phase aqueuse deux fois avec 50 cm³ de trichlorométhane. Les phases organiques réunies sont séchées sur sulfate de magnésium puis concentrées à sec sous pression réduite (5,2 kPa).

The N- (2,6-dimethylphenyl) N- (benzyl-1 piperidyl-4) fluoro-4 benzamide can be prepared in the following manner:

• To a solution of 6.5 g of N- (2,6-dimethylphenyl) (1-benzyl-4-piperidyl) amine in 100 cm ³ of trichloromethane, 4.5 cm ³ of triethylamine is added, then 3.1 cm ³ of 4-fluoro benzoic acid chloride, maintaining at + 25 ° C. After 30 minutes, 100 cm ³ of water are poured in, then after 16 hours, the water phase is decanted and reextracted twice with 50 cm ³ of trichloromethane. The combined organic phases are dried over magnesium sulfate and then concentrated to dryness under reduced pressure (5.2 kPa).

The oil obtained is chromatographed on a column 6 cm in diameter containing 500 g of silica gel, first eluting with 2750 cm ³ of the dichloromethane-ethanol mixture (98-2 by volume) and then of the same mixture of solvents ( 95-5 by volume). Fractions of 125 cm ^{3 are} collected ^. The fractions between 3500 and 4500 cm ³ are concentrated to dryness. 8.7 g of N- (benzyl-1 piperidyl-4) N- (2,6-dimethylphenyl) fluoro-4 benzamide are obtained in the form of a brown lacquer.

• - 6,95 à 7,4 (Mt, 12H aromatiques)
• - 3,9 (Mt, 1H :
  
  CH-N
  
  de la pipéridine)
• - 3,47 (S, 2H :
  
  N-CH₂- exo)
• - 2,86 (D large, J = 12,5, 2H, H équatoriaux des
  
  N-CH₂- de la pipéridine)
• - 2,23 (S, 6H, Ar-CH3)
• - 2,03 (DT, J = 12,5 et 3, 2H : H axiaux des
  
  N-CH₂- de la pipéridine)
• - 1,7 à 1,9 (Mt, 4H, -CH₂- de la pipéridine).

NMR spectrum (300 MHz, DMSO d6, δ in ppm, J in Hz)

• - 6.95 to 7.4 (Mt, 12H aromatic)
• - 3.9 (Mt, 1H:
  
  CH-N
  
  piperidine)
• - 3.47 (S, 2H:
  
  N-CH ₂ - exo)
• - 2.86 (D wide, J = 12.5, 2H, H equatorial of
  
  N-CH ₂ - piperidine)
• - 2.23 (S, 6H, Ar-CH3)
• - 2.03 (DT, J = 12.5 and 3.2H: axial H of
  
  N-CH ₂ - piperidine)
• - 1.7 to 1.9 (Mt, 4H, -CH ₂ - of piperidine).

N- (2,6-dimethylphenyl) N- (1-benzyl-piperidyl-4) amine can be prepared as follows:

To a solution of 18.9 g of N-benzylpiperidone-4 in 100 cm ³ of toluene, 14.8 cm ³ of 2,6-dimethyl aniline are added for 2 hours, collecting the water formed using a "Dean-Stark". The toluene is evaporated under reduced pressure (5.2 kPa).

The oil obtained is dissolved in 100 cm ³ of methanol and added to a mixture of 12.65 g of sodium cyanoborohydride and 13.6 g of zinc chloride in 150 cm ³ of methanol, at a temperature below 20 C After 2 hours at 20 ° C., 50 cm ³ of 10N sodium hydroxide solution are poured in, 100 cm ³ of water are added and the mixture is heated at reflux for 30 minutes. It is cooled to room temperature for 16 hours and 200 cm ³ of dichloromethane are added. The aqueous phase is decanted and reextracted twice with 100 cm ³ of dichloromethane. The organic phases are combined and dried over magnesium sulfate and then concentrated to dryness (5.2 kPa). The oil obtained is chromatographed on a column 7 cm in diameter containing 900 g of silica gel, first eluting with 2500 cm ³ of pure dichloromethane and then of dichloromethane-ethanol mixture (97-3 by volume), and collecting 250 cm ³ fractions ^. The fractions between 7250 cm ³ and 10500 cm ³ combined are concentrated to dryness to give 6.5 g of N- (2,6-dimethylphenyl) N- (1-benzyl-4-piperidyl) amine, in the form of a brown oil.

• - 6,75 à 7,45 (Mt, 8H aromatiques)
• - 3,54 (S, 2H,
  
  N-CH₂- exo)
• - 3,02 (Mt, 1H,
  
  N-CH
  
  de la pipéridine)
• - 2,92 (D large, J = 12,5, 2H, H équatoriaux des
  
  N-CH₂- de la pipéridine)
• - 2,77 (Mf, 1 H, -NH-)
• - 2,3 (S, 6H, Ar-CH₃)
• - 2,03 (DT, J = 12,5 et 2, 2H : H axiaux des
  
  N-CH₂- de la pipéridine)
• - 1,93 (D large, J = 12,5, 2H : H équatoriaux des -CH₂- de la pipéridine)
• - 1,5 (Mt, 2H : H axiaux des -CH₂- de la pipéridine).

NMR spectrum (250 MHz, CDCl ₃ , 5 ppm and J in Hz)

• - 6.75 to 7.45 (Mt, 8H aromatic)
• - 3.54 (S, 2H,
  
  N-CH ₂ - exo)
• - 3.02 (Mt, 1H,
  
  N-CH
  
  piperidine)
• - 2.92 (D wide, J = 12.5, 2H, H equatorial of
  
  N-CH ₂ - piperidine)
• - 2.77 (Mf, 1 H, -NH-)
• - 2.3 (S, 6H, Ar-CH ₃ )
• - 2.03 (DT, J = 12.5 and 2.2H: axial H of
  
  N-CH ₂ - piperidine)
• - 1.93 (D wide, J = 12.5, 2H: H equatorials of -CH ₂ - of piperidine)
• - 1.5 (Mt, 2H: axial H of -CH ₂ - of piperidine).

EXAMPLE 8

The procedure is as in Example 4, but starting with 1.6 g of (2-bromo-ethyl) -4-3,4-dihydro-2H-benzopyran, 2.95 g of N- (4-chloro-phenyl) hydrochloride N- (piperidyl-4) methanesulfonamido-4 benzamide, 0.9 g of dry potassium carbonate and 0.8 g of potassium iodide in 50 cm ³ of butanone-2. The residue obtained is taken up in 100 cm ³ of ethanol and 6.6 cm ³ of a 1 N solution of hydrochloric acid and then concentrated until the start of crystallization. The white precipitate formed is filtered through sintered glass and is then recrystallized without 100 cm ³ of methanol.

2.1 g of N - {[(3,4-dihydro-3,4H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} N- (4-chloro-phenyl) methanesulfonamido-4 hydrochloride are thus obtained. benzamide melting around 260 C.

EXAMPLE 9

The procedure is as in Example 4, but starting from 1.6 g of (2-bromo-ethyl) -4-3,4-dihydro-2H-benzopyran, 2.42 g of N- (4-chloro-phenyl) hydrochloride N-piperidyl-4 phenylacetamide, 1.80 g of dry potassium carbonate and 0.80 g of potassium iodide in 50 cm ³ of butanone-2.

The oil obtained is taken up in the minimum amount of acetone and 0.6 g of oxalic acid dissolved in acetone is added. The white precipitate formed is filtered through sintered glass and then recrystallized from 50 cm ³ of ethanol.

2.3 g of N - {[dihydro-3,4 2H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} N- (4-chloro-phenyl) phenylacetamide are thus obtained. form a white solid melting at 185 C.

N- (4-chloro-phenyl) N- (piperidyl-4) phenylacetamide hydrochloride was prepared by analogy with N- (3-chloro-phenyl) N- (piperidyl-4) phenylacetamide Chem. Abstr., 93 132380.

EXAMPLE 10

The procedure is as in Example 1, but starting with 1.94 g of (2-bromo-ethyl) -4 dihydro-3,4 2H-benzopyran, 2.21 g of N-isopropyl N- hydrochloride (piperidyl -4) fluoro-4 benzamide, 3.05 g of dry potassium carbonate and 1.22 g of potassium iodide in 20 cm ³ of butanone-2, stirring for 4 hours 30 minutes. The butanone is evaporated under reduced pressure (5.2 kPa), and the residue is taken up in 50 cm ³ of water which is extracted with 50 cm ³ and then twice 25 cm ³ of dichloromethane. The combined organic phases are dried over dry magnesium sulfate and then concentrated to dryness under reduced pressure (5.2 kPa). The oil obtained is chromatographed on a column 3 cm in diameter containing 100 g of silica gel, eluting with a dichloromethane-ethanol mixture (95-5 by volume) and collecting 25 cm ³ fractions ^. The fractions included between 150 and 950 cm ³ are concentrated to dryness. The oil obtained is dissolved in 30 cm ³ of ethyl acetate and added with 1.5 cm ³ of a solution of 5N hydrochloric acid in isopropanol.

3 g of N - {[(3,4-dihydro-3,4H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} N-isopropyl fluoro-4 benzamide, in the form of a white solid melting at 165 "C.

• A une solution de 3,35 g de N-(benzyl-1 pipéridyl-4) N-isopropyl fluoro-4 benzamide dans 100 cm³ d'éthanol absolu, on additionne 20 cm³ d'acide chlorhydrique aqueux 3N puis 1,5 g de palladium sur charbon à 10 %. Cette suspension est soumise à l'action de l'hydrogène, sous pression atmosphérique à une température de 55 C. Après 4 heures, le volume théorique a été absorbé. On refroidit et filtre le catalyseur qui est lavé à l'éthanol puis à l'eau. On évapore l'éthanol sous pression réduite (5,2 kPa). Le solide obtenu est recristallisé dans 20 cm³ d'éthanol absolu.

N-isopropyl hydrochloride, N- (piperidyl-4) fluoro-4 benzamide can be prepared as follows:

• To a solution of 3.35 g of N- (1-benzyl-4-piperidyl) N-isopropyl 4-fluoro benzamide in 100 cm ³ of absolute ethanol, 20 cm ³ of 3N aqueous hydrochloric acid are added, followed by 1.5 g of 10% palladium on charcoal. This suspension is subjected to the action of hydrogen, at atmospheric pressure at a temperature of 55 C. After 4 hours, the theoretical volume has been absorbed. The catalyst is cooled and filtered, which is washed with ethanol and then with water. The ethanol is evaporated off under reduced pressure (5.2 kPa). The solid obtained is recrystallized from 20 cm ³ of absolute ethanol.

2.6 g of N-isopropyl N- (4-piperidyl-4) fluoro-4 benzamide hydrochloride are thus obtained in the form of a white solid melting above 260 C.

• - 1,2 (Mf, 6H, -CHa de l'isopropyle)
• -1,7 (D large, J = 16, 2H, - H équatoriaux des -CH₂- de la pipéridine)
• -2,65 à 3,20 (Mt, 4H, H axiaux des -CH₂- et des
  
  N-CH₂- de la pipéridine)
• - 3,28 (D large, J = 16, H équatoriaux des
  
  N-CH₂- de la pipéridine)
• -3,4 à 3,8 (Mt, 2H,
  
  CH-N
  
  de la pipéridine et - -H-isopropyle)
• -7,2 à 7,5 (Mt, aromatiques)

NMR spectrum (200 MHz, DMSO d6, ô in ppm and J in Hz):

• - 1.2 (Mf, 6H, -CHa of isopropyl)
• -1.7 (D wide, J = 16, 2H, - H equatorial of -CH ₂ - of piperidine)
• -2.65 to 3.20 (Mt, 4H, axial H of -CH ₂ - and
  
  N-CH ₂ - piperidine)
• - 3.28 (D wide, J = 16, H equatorial of
  
  N-CH ₂ - piperidine)
• -3.4 to 3.8 (Mt, 2H,
  
  CH-N
  
  piperidine and - -H-isopropyl)
• -7.2 to 7.5 (Mt, aromatics)

• A une solution de 3,83 g de dichlorhydrate hydraté de benzyl-1 isopropylamino-4 pipéridine et de 15 cm³ de triéthylamine dans 50 cm³ de trichlorométhane, on additionne 3,7 cm³ de chlorure de l'acide fluoro-4 benzoïque. Après 6 heures d'agitation à 20° C, on verse 50 cm³ d'eau et laisse reposer pendant 16 heures. On décante et extrait la phase aqueuse avec 50 cm³ de trichlorométhane. Les phases organiques sont lavées avec 50 cm³ d'eau puis séchées sur sulfate de magnésium, et concentrées à sec sous pression réduite (5,2 kPa). L'huile obtenue est chromatographiée sur une colonne de 4 cm de diamètre contenant 200 g de gel de silice, en éluant d'abord avec 1400 cm³ d'un mélange dichlorométhane-éthanol (95-5 en volumes) et en recueillant des fractions de 60 cm^3. Les fractions comprises entre 480 et 1980 cm³ sont concentrées à sec pour donner un solide ocre que l'on recristallise dans un mélange éther dilsopropylique- éthanol (95-5 en volumes) pour obtenir 1,2 g de N-(benzyl-1 pipéridyl-4) N-isopropyl fluoro-4 benzamide, sous la forme d'un solide blanc fondant à 98° C.

N- (1-benzyl-piperidyl-4) N-isopropyl fluoro-4 benzamide can be prepared in the following manner:

• To a solution of 3.83 g of 1-benzyl-4-isopropylamino-4 piperidine dihydrochloride and 15 cm ³ of triethylamine in 50 cm ³ of trichloromethane, 3.7 cm ³ of 4-fluoro benzoic acid chloride are added . After 6 hours of stirring at 20 ° C, 50 cm ³ of water are poured in and left to stand for 16 hours. The aqueous phase is decanted and extracted with 50 cm ³ of trichloromethane. The organic phases are washed with 50 cm ³ of water and then dried over magnesium sulfate, and concentrated to dryness under reduced pressure (5.2 kPa). The oil obtained is chromatographed on a column 4 cm in diameter containing 200 g of silica gel, first eluting with 1400 cm ³ of a dichloromethane-ethanol mixture (95-5 by volume) and collecting fractions of 60 cm ^3. The fractions between 480 and 1980 cm ³ are concentrated to dryness to give an ocher solid which is recrystallized from a mixture of dilsopropyl ether-ethanol (95-5 by volume) to obtain 1.2 g of N - (1-benzyl-piperidyl-4) N-isopropyl fluoro-4 benzamide, in the form of a white solid, melting at 98 ° C.

• A une solution de 6,8 g de chlorhydrate de N-benzyl pipéridone-4 dans 100 cm³ d'éthanol, on additionne 14,3g de chlorhydrate d'isopropylamine et refroidit à + 10 °C. On additionne alors 1,9 g de cyanoborohydrure de sodium puis agite 16 heures à 20 C.

Benzyl-1 isopropylamino-4 piperidine dihydrochloride can be prepared as follows:

• To a solution of 6.8 g of N-benzyl piperidone-4 hydrochloride in 100 cm ³ of ethanol, 14.3 g of isopropylamine hydrochloride are added and the mixture is cooled to + 10 ° C. 1.9 g of sodium cyanoborohydride are then added and the mixture is stirred for 16 hours at 20 C.

50 cm ³ of 10N sodium hydroxide are poured in and the mixture is stirred for 22 hours at 20 ° C. The ethanol is evaporated off under reduced pressure (5.2 kPa) and the residual oil is extracted three times with 50 cm ³ of dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated to dryness. The residual oil is dissolved in 50 cm ³ of absolute ethanol and added with 11.5 cm ³ of a 5N solution of hydrochloric acid in isopropanol. 4.24 g of hydrated 1-benzyl-4-isopropylamino-4 piperidine dihydrochloride are thus obtained in the form of a white solid, melting above 260 ° C.

• - 7,30 à 7,80 (Mt : 5H aromatiques)
• - 4,26 et 4,46 (D et AB limite : 2H en totalité et dans un rapport 85/15 respectivement ; N-CH₂- exo)
• - 2,80 à 3,50 (Mt, 6H :
  
  N-CH₂- et
  
  N-CH
  
  de la pipéridine et
  
  CH- de l'isopropyle)
• - 1,90 à 2,30 (Mt, 4H : -CH₂- de la pipéridine)
• - 1,28 et 1,32 (2D, J = 7, 6H en totalité et dans un rapport 85/15 respectivement, -CH₃ de l'isopropyle).

NMR spectrum (200MHz, DMSO d6, 5 in ppm and J in Hz)
(At ordinary temperature, a mixture of two conformers is observed in the proportions 85/15)

• - 7.30 to 7.80 (Mt: 5H aromatic)
• - 4.26 and 4.46 (D and AB limit: 2H in total and in an 85/15 ratio respectively; N-CH ₂ - exo)
• - 2.80 to 3.50 (Mt, 6H:
  
  N-CH ₂ - and
  
  N-CH
  
  piperidine and
  
  CH- isopropyl)
• - 1.90 to 2.30 (Mt, 4H: -CH ₂ - piperidine)
• - 1.28 and 1.32 (2D, J = 7.6H in total and in a ratio 85/15 respectively, -CH ₃ of isopropyl).

EXAMPLE 11

The procedure is as in Example 4, but starting with 1.6 g of (2-bromo-ethyl) -4 dihydro-3,4 2H-benzopyran, 2.4 g of phenyl-1 hydrochloride (piperidyl-4) -1 (2,6-dimethylphenyl) -3 urea, 1.8 g of dry potassium carbonate and 0.8 g of potassium iodide in 50 cm ³ of butanone-2.

The solid residue obtained is taken up in the minimum amount of acetone and 0.6 g of oxalic acid dissolved in acetone is added.

The white precipitate formed is filtered through sintered glass and is then recrystallized from 150 cm ³ of 95% aqueous ethanol.

2.1 g of {[dihydro-3,4 2H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} -1 phenyl-1 (2,6-dimethyl-2,6-phenyl) are thus obtained. ) -3 urea in the form of a white powder melting with decomposition at 190 ° C.

Phenyl-1 (piperidyl-4) -1 (2,6-dimethylphenyl) -3 urea hydrochloride is prepared by analogy with the method described in Chem. Abstr. 88, 022640.

EXAMPLE 12

The procedure is as in Example 1, but starting from 2.65 g of (2-bromo-ethyl) -4 dihydro-3,4 2H-benzopyran, from 2.46 g of N- (2,6-dimethylphenyl ) piperidine-4 acetamide, 2.76 g of carbonate dry potassium, 1.66 g of potassium iodide in 25 cm ³ of dry dimethylformamide, in hot heat for 4 hours at 60 C. The dimethylformamide is evaporated under reduced pressure (1 kPa) and the residue is taken up in 50 cm ³ of water which is extracted three times with 50 cm ³ of dichloromethane. The combined organic phases are dried over magnesium sulfate and then concentrated to dryness under reduced pressure (5 kPa). The solid obtained is chromatographed on a column 4 cm in diameter, containing 120 g of silica gel, eluting with a toluene-diethylamine mixture (95-5 by volume) and collecting 25 cm ³ fractions. The fractions between 175 and 1000 cm ³ are concentrated to dryness. the solid obtained is recrystallized from 20 cm ³ of acetone.

2.55 g of [(dihydro-3,4 2H-benzopyran-1 yl-4) -2 ethyl] -1 N- (2,6-dimethylphenyl) piperidine-4 acetamide, in the form of a white solid melting at 136 ° C.

N- (2,6-dimethylphenyl) piperidine-4 actamide is prepared as described in Chem. Abstr., 76, 152718x.

EXAMPLE 13

The procedure is as in Example 1, but starting with 2.41 g of (2-bromo-ethyl) -4-3,4-dihydro-2H-benzopyran, 2.64 g of N- (nicotinoyl) piperazine dihydrochloride, 4.15 g of dry potassium carbonate and 1.66 g of potassium iodide in 25 cm ³ of butanone-2, heating for 3 hours 30 minutes.

The butanone is evaporated under reduced pressure (5.2 kPa) and the oil obtained is taken up in 50 cm ³ of water which is extracted with 50 cm ³ and then twice 25 cm ³ of dichloromethane. The combined organic phases are dried over magnesium sulfate and then concentrated to dryness under reduced pressure (5.2 kPa).

The oil obtained is chromatographed on a column 4 cm in diameter containing 200 g of silica gel, eluting with a toluene-diethylamine mixture (95-5 by volume) and collecting 60 cm ³ fractions. the fractions between 1140 and 1500 cm ³ are concentrated to dryness.

The oil obtained is dissolved in 20 cm ³ of absolute ethanol and added with 2.5 cm ³ of a 5N solution of hydrochloric acid in isopropanol.

2.35 g of [(dihydro-3,4 2H-benzopyran-1 yl-4) -2 ethyl] -1 nicotinoyl-4 piperazine monohydrate are thus obtained 2.35 g of hydrochloride, in the form of white crystals melting at 190 ° C. decomposing.

The N- (nicotinoyl) piperazine is prepared as described in Chem. Abstr., 42, 6002g (1948).

EXAMPLE 14

The procedure is as in Example 1, but starting with 2.9 g of (2-bromo-ethyl) -4 dihydro-3,4 2H-benzopyran, 2.05 g of 4-benzoyl piperidine, 3 g of dry potassium carbonate, 1.8 g potassium iodide, in 25 cm ³ of butanone-2, heating for 1 hour 30 minutes. The butanone is evaporated under reduced pressure (5.2 kPa) and the oil obtained is taken up in 50 cm ³ of water which is extracted with 50 cm ³ and then twice 25 cm ³ of dichloromethane. The combined organic phases are dried over magnesium sulphate then concentrated to dryness under reduced pressure (5.2 XPa). The oil obtained is chromatographed on a column 4 cm in diameter containing 200 g of silica gel, eluting with a dichloromethane-ethanol mixture (95-5 by volume), and collecting 60 cm ³ fractions ^. The fractions between 360 and 1560 cm ³ are concentrated to dryness (5.2 kPa). The oil obtained is dissolved in 40 cm ³ of acetone and added with 2.2 cm ³ of a 5N solution of hydrochloric acid in isopropanol.

2.65 g of benzoyl-4 hydrochloride [[3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl] -1 piperidine are thus obtained in the form of a white solid melting at 210 ° C. decomposing.

EXAMPLE 15

The procedure is as in Example 1, but starting with 2.41 g of (2-bromo-ethyl) -4-3,4-dihydro-2H-benzopyran, 3.8 g of (4-fluoro-benzoyl) paratoluenesulfonate - 4 piperidine, 2.75 g of dry potassium carbonate, 1.66 g of potassium iodide, in 25 cm ³ of butanone-2, heating for 2 hours. The butanone is evaporated under reduced pressure (5.2 kPa) and the oil obtained is taken up in 50 cm ³ of water which is extracted with 50 cm ³ and then twice 25 cm ³ of dichloromethane. the combined organic phases are dried over magnesium sulphate and then concentrated to dryness under reduced pressure (5.2 kPa). The solid obtained is dissolved in 70 cm ³ of warm acetone and added with 2.1 cm ³ of a 5N acid solution hydrochloric acid in isopropanol.

3 g of [(dihydro-3,4 2H-benzopyran-1 yl-4) -2 ethyl] -1 (4-fluoro-benzoyl) -4 piperidine hydrochloride are thus obtained in the form of a white solid melting at 220 C by decomposing.

EXAMPLE 16

The procedure is as in Example 4, but starting with 1.5 g of (2-bromo-ethyl) -4-3,4-dihydro-2H-benzopyran, 2.16 g of (4-piperidyl-carbonyl) acid oxalate -3 indole, 1.71 g of dry potassium carbonate and 1.085 g of potassium iodide in 50 cm ³ of butanone. The residue obtained is taken up hot with 20 cm ³ of ethanol and 6.2 cm ³ of a 1N solution of hydrochloric acid and then concentrated until the start of crystallization. The precipitate formed is filtered through sintered glass and is then recrystallized from 50 cm ³ of 95% ethanol. 0.68 g of N - {[(3,4-dihydro-3,4H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} carbonyl-3 indole in the form of a white powder is thus obtained. melting at 240 ° C. The (piperidyl-4) carbonyl-3 indole is prepared according to the technique described in Chem. Abstr., 64, 14161f.

EXAMPLE 17

To a solution of 0.63 g of benzoyl-4 hydrochloride [(3,4-dihydro-2H-benpyran-1 yl-4) -2 ethyl] -1 piperidine and 3.3 cm ³ of a sodium hydroxide solution N in 20 cm ³ of absolute ethnaol, 0.3 g of hydroxylamine hydrochloride is added and the mixture is stirred at + 20 ° C for 16 hours. The solvents are evaporated under reduced pressure (5.2 kPa) and the residue is taken up in 25 cm ³ of water which is extracted three times with 25 cm ³ of dichloromethane. The combined organic phases are dried over magnesium sulfate and then concentrated to dryness under reduced pressure. The solid obtained is dissolved in 10 cm ³ of boiling acetone and added with 0.12 g of oxalic acid which is dissolved at boiling point.

0.37 g of {[(3,4-dihydro-3,4H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} phenyl methanoxin (Z + E) acid oxalate is thus obtained in the form of a white solid melting from 130 ° C.

EXAMPLE 18

1.03 cm3 is added to a solution cooled to 0 to 5 ° C. of 1.64 g of [(dihydro-3,4 2H-benzopyran-1 yl-4) -2 ethyl] -1 piperazine in 25 cm3 of dichloromethane of triethylamine and then 0.85 cm3 of benzenesulfonic acid chloride is introduced dropwise.

After 2 hours at 20 ° C., dilution is carried out with 10 cm 3 of distilled water and an identical amount of a 1 N sodium hydroxide solution is added, then extracted twice with 10 cm 3 of dichloromethane. The organic phase is dried over magnesium sulfate and then concentrated to dryness under reduced pressure (5.2 kPa).

The residue obtained is chromatographed on a column 3 cm in diameter containing 60 g of silica gel, eluting with a dichloromethane-acetone mixture (70-30 by volume) and collecting 30 cm3 fractions. The fractions between 90 and 210 cm3 are concentrated to dryness under reduced pressure (5.2 kPa).

The oil obtained is taken up in 20 cm3 of ethanol and added 3 cm3 of a 5N solution of hydrochloric acid in isopropanol, concentrated to dryness and recrystallized from 40 cm3 of butanone-2. 1.45 g of [(dihydro-3,4 2H-benzopyran-1 yl-4) -2 ethyl] -1 (phenylsulfonyl) -4 piperazine hydrochloride are thus obtained in the form of a white solid, melting at 164 ° C. .

• On opère comme à l'exemple 1 à partir de 9,7 g de (bromo-2 éthyl)-4 dihydro-3,4 2H-benzopyranne, de 10,4 g de pipérazine puis de 13,4 g d'iodure de potassium dans 300 cm3 de butanone-2 mais sans adjonction de carbonate de potassium. L'huile obtenue est chromatographiée sur une colonne de 4,4 cm de diamètre contenant 100 g de gel de silice en utilisant comme éluant un mélange dichlorométhane -éthanol - diéthylamine (80-18-2 en volumes). Les fractions comprises entre 200 et 500 cm3 sont concentrées à sec.
• On obtient ainsi 7,1 g de [dihydro-3,4 2H-benzopyran-1 yl-4)-2 éthyl]-1 pipérazine sous forme d'une huile qui est utilisée telle quelle pour l'étape suivante.

[(3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl] -1 piperazine can be prepared as follows:

• The operation is carried out as in Example 1 from 9.7 g of (2-bromo-ethyl) -4 dihydro-3,4 2H-benzopyran, 10.4 g of piperazine then 13.4 g of iodide of potassium in 300 cm3 of butanone-2 but without the addition of potassium carbonate. The oil obtained is chromatographed on a 4.4 cm diameter column containing 100 g of silica gel using a dichloromethane -ethanol-diethylamine mixture (80-18-2 by volume) as eluent. The fractions between 200 and 500 cm3 are concentrated to dryness.
• 7.1 g of [dihydro-3,4 2H-benzopyran-1 yl-4) -2 ethyl] -1 piperazine are thus obtained in the form of an oil which is used as it is for the following step.

EXAMPLE 19

2.85 g of [(dihydro-3,4 2H-benzopyran-1 yl-4) -2 ethyl] -1 piperazine, 2 g of N- (2,6-dimethylphenyl) are heated at reflux for 12 hours. ) 3-chloro-propionamide, 1.23 g of dry potassium carbonate and 1.48 g of potassium iodide in 70 cm3 of butanone-2.

The reaction mixture is filtered on sintered glass and then the solvent is evaporated off under reduced pressure (5.2 kPa). The oil obtained is taken up in 15 cm3 of a 1N sodium hydroxide solution and then extracted twice with 150 cm3 of dichloromethane. The organic phase is then washed with water and then dried over magnesium sulfate.

After evaporation, an oil is obtained which is purified by chromatography on a 4.4 cm diameter column containing 100 g of silica gel, eluting with a dichloromethane-isopropanol mixture (80-20 by volume) and collecting fractions of 50 cm3. The fractions between 1.3 and 2 liters are concentrated to dryness.

After recrystallization from isopropyl acetate, 1 g of {[(3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl] -1 piperazinyl-4} N- (2,6-dimethyl) is obtained. phenyl) propanamide in the form of a white solid, melting at 130 ° C.

N- (2,6-dimethylphenyl) 3-chloro-propanamide can be prepared according to the method described in Beil, 12 III, 2464.

EXAMPLE 20

The procedure is as in Example 19, but starting with 2 g of [(3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl] -1 piperazine, 1.6 g of N- (dimethyl- 2.6 phenyl) chloroacetamide, 1.12 g of dry potassium carbonate and 1.34 g of potassium iodide in 80 cm3 of butanone-2.

After 2 hours 30 minutes of reflux, a residue is obtained which is chromatographed on a 4.4 cm diameter column containing 100 g of silica gel and using an ethyl acetate / ethanol mixture (90-10 by volume) as eluent and collecting 25 cm3 fractions. The fractions between 475 and 1000 cm3 are concentrated to dryness under reduced pressure (5.2 kPa).

The oil obtained is taken up in 30 cm3 of ethanol and 1.3 cm3 of a 5.5N solution of hydrochloric acid in isopropanol are added.

After crystallization, 1 g of {[(3,4-dihydro-3,4H-benzopyran-1 yl-4) -2 ethyl] -1 piperazinyl-4} N- (2,6-dimethylphenyl) acetamide hydrochloride is obtained. of a solid white melting around 230 C.

N- (2,6-dimethylphenyl) chloroacetamide can be prepared according to the method described in Beil., 12 III, 2464.

EXAMPLE 21

The procedure is as in Example 4, but starting with 1.9 g of (2-bromo-ethyl) -4-3,4-dihydro-2H-benzopyran, 2 g of N- (piperidyl-4) fluoro- hydrochloride 4 benzamide, 2.15 g of dry potassium carbonate and 0.95 g of potassium iodide in 60 cm ³ of butanone-2. The yellow oil obtained is purified by chromatography on a column 4 cm in diameter containing 110 g of silica gel, eluting with 300 cm ³ of a toluene-diethylamine-ethanol mixture (60-20-20 by volume) and collecting fractions of 30 cm ^3. The fractions between 330 and 900 cm ³ are concentrated to dryness. The yellow crystals obtained are dissolved in 25 cm ³ of acetone and added with 3 cm ³ of a 3.4N solution of hydrochloric acid in isopropanol. The precipitate formed is filtered on sintered glass and then recrystallized from 80 cm ³ of an ethanol-acetone mixture (20-60 by volume). After addition of 10 cm ³ of ethyl ether, 2.05 g of N - {[(3,4-dihydro-3,4H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} fluoro- hydrochloride are obtained. 4 benzamide in the form of a white crystalline solid melting at 240 C.

• 2,70 g de chlorhydrate de N-(benzyl-1 pipéridyl-4) fluoro-4 benzamide dans 50 cm³ d'éthanol à 95 % sont hydrogénés à 60 C, sous pression atmosphérique, en présence de 0,6 g d'hydroxyde de palladium. Après filtration sur Kieselguhr et concentration à sec sous pression réduite (5,2 kPa) on obtient des cristaux blancs qui sont utilisés tels quels dans l'étape suivante.

N- (piperidyl-4) fluoro-4 benzamide hydrochloride can be prepared as follows:

• 2.70 g of N- (1-benzyl-4-piperidyl-4) fluoro-4 benzamide hydrochloride in 50 cm ³ of 95% ethanol are hydrogenated at 60 ° C., at atmospheric pressure, in the presence of 0.6 g of palladium hydroxide. After filtration through Kieselguhr and concentration to dryness under reduced pressure (5.2 kPa), white crystals are obtained which are used as such in the next step.

• 2 g d'amino-4 benzyl pipéridine dissous dans 20 cm³ de dichlorométhane sont agités pendants 2 heures à 0" C avec 1,30 cm³ du chlorure de l'acide fluoro-4 benzoïque en présence de 1,5 cm³ de

triéthylamine. après 18 heures à température ambiante, le mélange réactionnel est lavé par une solution ammoniacale à 30 % puis à l'eau jusqu'à pH neutre. la phase organique est ensuite séchée sur sulfate de magnésium puis concentrée sous pression réduite (5,2 kPa).The N- (1-benzyl-4-piperidyl-4) fluoro-4-benzamide hydrochloride can be prepared in the following manner:

• 2 g of 4-amino benzyl piperidine dissolved in 20 cm ³ of dichloromethane are stirred for 2 hours at 0 "C with 1.30 cm ³ of 4-fluoro benzoic acid chloride in the presence of 1.5 cm ³ of

triethylamine. after 18 hours at room temperature, the reaction mixture is washed with a 30% ammonia solution and then with water until neutral pH. the organic phase is then dried over magnesium sulfate and then concentrated under reduced pressure (5.2 kPa).

The yellow crystals obtained are purified by chromatography on a column 4 cm in diameter containing 70 g of silica gel, eluting with 480 cm ³ of a toluene-diethylamine-ethanol mixture (80-10-10 by volume) and collecting fractions of 30 cm ^3. The fractions between 120 cm ³ and 4800 cm ³ are concentrated to dryness.

The white crystals obtained are taken up in 20 cm ³ of dichloromethane and 3 cm ³ of a 3.5N solution of hydrochloric acid in isopropanol. 2.70 g of hydrochloride of N- (1-benzyl-4-piperidyl-4) fluoro-4 benzamide are thus obtained, melting at 236 C.

EXAMPLE 22

The procedure is as in Example 4, but starting from 0.70 g (2-bromo-ethyl) -4-3,4-dihydro-2H-benzopyran, 0.75 g of N-phenyl N- hydrochloride (4-piperidyl ) methanesulfonamide, 0.75 g of dry potassium carbonate and 0.35 g of potassium iodide in 45 cm ³ of butanone-2. The yellow oil obtained is purified by chromatography on a column 4 cm in diameter containing 60 g of silica gel, eluting with 660 cm ³ of a dichloromethane-ethanol mixture (95-5 by volume) and collecting 30 fractions. cm ³ . The fractions between 120 cm ³ and 660 cm ³ are concentrated to dryness. The oil obtained is taken up in 10 cm ³ of ethanol and 0.35 g of fumaric acid dissolved in 10 cm ³ of ethanol is added. Concentrate to dryness, wash the crystals with acetone and recrystallize from 20 cm ³ of isopropanol.

0.310 g of {[(3,4-dihydro-3,4H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} N-phenyl methanesulfonamide acid fumarate is thus obtained in the form of a white solid melting at 186 ° C.

• 1,16 g de chlorhydrate de N-(benzyl-1 pipéridyl-4) N-phényl méthanesulfonamide dans 50 cm³ d'éthanol à 95 % sont hydrogénés à 60⁰ C, sous pression atmosphérique, en présence de 0,3 g d'hydroxyde de palladium.

N-phenyl N- (piperidyl-4) methanesulfonamide hydrochloride can be prepared as follows:

• 1.16 g of N- (1-benzyl-piperidyl-4) N-phenyl methanesulfonamide hydrochloride in 50 cm ³ of 95% ethanol are hydrogenated at 60 ^° C., at atmospheric pressure, in the presence of 0.3 g of palladium hydroxide.

After filtration through Kieselguhr and concentration to dryness under reduced pressure (5.2 kPa), 0.758 g of white crystals are obtained which are used as such in the following step.

• 5,8 g de benzyl-1 anilino-4 pipéridine dissous dans 40 cm³ de dichlorométhane sont agités sous argon pendant 7 heures à 0 ° C avec 2 cm³ de chlorure de l'acide méthanesulfonique et en présence de 3 cm³ de triéthylamine. Après traitement comme décrit à l'exemple 21, on isole une huile qui est chromatographiée par CLHP (sur Waters Prep. 500 avec une colonne Prep. PAK de 5 cm de diamètre et 30 cm de longueur contenant de la silice 55-105 α) en utilisant comme éluant le mélange dichlorométhane-acétate d'isopropyle (5-1 en volumes) et en recueillant les fractions comprises entre 1500 cm³ et 2350 cm³.

The N- (1-benzyl-4-piperidyl) N-phenyl methanesulfonamide can be prepared as follows:

• 5.8 g of 1-benzyl-4-anilino piperidine dissolved in 40 cm ³ of dichloromethane are stirred under argon for 7 hours at 0 ° C. with 2 cm ³ of methanesulfonic acid chloride and in the presence of 3 cm ³ of triethylamine . After treatment as described in Example 21, an oil is isolated which is chromatographed by HPLC (on Waters Prep. 500 with a Prep. PAK column 5 cm in diameter and 30 cm in length containing 55-105 α silica) using the dichloromethane-isopropyl acetate mixture (5-1 by volume) as eluent and collecting the fractions between 1500 cm ³ and 2350 cm ³ .

1.05 g of N- (1-benzyl-4-piperidyl) N-phenyl methanesulfonamide are thus obtained in the form of a white solid, melting at 125 ° C.

Benzyl-1 anilino-4 piperidine was prepared according to the method described in Dutch patent application 65 06 574.

EXAMPLE 23

The procedure is as in Example 4, but starting with 1.6 g of (2-bromo-ethyl) -4-3,4-dihydro-2H-benzopyran, 2.34 g of N-phenyl N- hydrochloride (piperidyl- 4) benzenesulfonamide, 1.8 g of dry potassium carbonate and 0.8 g of potassium iodide in 50 cm ³ of butanone-2.

The oil obtained is taken up in the minimum amount of ethanol and 1 g of benzenesulfonic acid dissolved in ethanol is added. The white precipitate formed is filtered through sintered glass and then recrystallized from 80 cm ³ of ethanol-methanol mixture (50-50 by volume).

2.45 g of N - {benzenesulfonate are thus obtained. (3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} N-phenyl benzenesulfonamide in the form of a white solid melting at 150 ° C.

N-phenyl N- (piperidyl-4) benzenesulfonamide hydrochloride can be prepared as described in Example 22 for N-phenyl N- (piperidyl-4) methanesulfonamide.

The present invention also relates to pharmaceutical compositions consisting of a product of general formula (I) in free form or in the form of an addition salt with an acid. pharmaceutically acceptable, in the pure state or in the form of a combination with any other pharmaceutically compatible product, which may be inert or physiologically active. The compositions according to the invention can be used orally or parenterally.

As solid compositions for oral administration, tablets, pills, powders or granules can be used. In these compositions, the active product according to the invention (optionally combined with another pharmaceutically compatible product) is mixed with one or more inert diluents or adjuvants, such as sucrose, lactose or starch. These compositions can also include substances other than diluents, for example a lubricant such as magnesium stearate.

As liquid compositions for oral administration, there may be used pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil. These compositions can also include substances other than diluents, for example wetting, sweetening or flavoring products.

The sterile compositions for parenteral administration may preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents, can be used. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in a sterile injectable medium.

The pharmaceutical compositions according to the invention which reduce disorders of the heart rhythm due to re-entry phenomena, treated or not, are particularly useful in human therapy in the treatments consecutive to myocardial infarction as well as in chronic angina and ischemic heart disease.

In general, the doctor will determine the dosage he considers most appropriate based on age, weight and other factors specific to the subject to be treated.

Generally the doses are between 0.25 and 1.5 g per day, of active product by oral or intravenous route for an adult.

The following examples, given without limitation, illustrate a composition according to the invention.

Example A

Tablets having the following composition are prepared:

Example B

The tablets having the following composition are prepared:

Claims (13)

1 - A new benzopyran derivative characterized in that it corresponds to the general formula:

in which - R, represents a hydrogen or halogen atom or a hydroxy, alkyloxy, nitro, amino, alkylsulphonamido or acylamino radical, - R represents 1) a radical of general formula:

in which R ₂ and R _{3, which are} identical or different, represent hydrogen or halogen atoms or hydroxy, alkyl, alkyloxy, amino, alkylsulfonamido or nitro radicals, or else 2) a radical of general formula:

in which n equals 0 or 1, R ₄ is a hydrogen atom, a radical. alkyl or a radical of structure:

in which R _s and R ₆ are hydrogen or halogen atoms or an alkyloxy radical and Q represents an acyl, alkylsulphonyl radical or a radical of structure:

in which R ₂ and R ₃ are defined as above, Y represents a carbonyl or sulfonyl radical and Z represents a single bond or a methylene or imino radical, or alternatively 3) a radical of general formula:

in which n equals 0 or 1, m equals 0 to 2, X is a carbon atom or X can be a nitrogen atom if n = 0, W represents a single bond or an imino radical and Ar represents a pyridyl radical, indolyl, quinolyl, 2-alkyl quinolyl or phenyl optionally substituted by radicals R ₂ and R ₃ as defined above, provided that m is other than 0 when X is a nitrogen atom or else 4) a radical of general formula:

in which R ₂ and R ₃ are defined as above and R ₇ represents a hydrogen atom or an alkyl radical, or else 5) a radical of formula:

- R and R are identical and represent hydrogen atoms or alkyl radicals, it being understood that the alkyl and acyl radicals and portions mentioned above contain 1 to 4 carbon atoms in straight or branched chain, in its isomeric forms and their mixtures, as well as its addition salts with acids. 2- A new benzopyran derivative according to claim 1, for which Ri, R and R are hydrogen atoms, and R represents a radical as defined in 1) for which Ri and R ₃ are hydrogen atoms, or R represents a radical as defined in 2) for which n equals O, R ₄ is a hydrogen atom or an alkyl radical or a radical of structure (IVa) in which R _s and R ₆ are hydrogen atoms or of halogen, or of the alkyloxy radicals and Q represents an acetyl, methylsulphonyl radical or a radical of general formula (IVb) in which Y is a carbonyl or sulphonyl radical and Z is a bond or a methylene or imino radical, and R ₂ and R ₃ are hydrogen or halogen atoms or alkyl or methylsulfonamido radicals, or R represents a radical as defined in 3) for which n equals 0, m equals 0 to 2, W is a bond or an imino radical, Ar is pyridyl, indolyl or phenyl optionally substituted by a halogen atoms, or radicals alkyl or alkyloxy and X is a carbon or nitrogen atom, or R represents a radical as defined in 4) for which R ₇ is a hydrogen atom. 3 - N - {[3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} acetanilide and its salts; 4 - [(3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl] -1 nicotinoyl-4 piperazine and its salts; 5 - N - {[3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} N-phenyl fluoro-4 benzamide and its salts; 6 - Benzoyl-4 [(3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl] -1 piperidine and its salts; 7 - {[3,4-dihydro-2H-benzopyran-1 yl-4) -2 ethyl] -1 piperidyl-4} phenyl methanoxime and its salts; 8 - Process for the preparation of a new benzopyran derivative according to claim 1, characterized in that a product of general formula is made to act: HR or its salt, in which R is defined as in claim 1, provided that n is equal to 0, and where appropriate the amino and / or hydroxy radicals contained in R being protected, on a benzopyran derivative of general formula:

in its isomeric forms or their mixtures, in which Ri, R and R "are defined as in claim 1, where appropriate R ₁ being protected, and Y ₁ represents a halogen atom or an alkylsulfonyloxy or arylsulfonyloxy radical, optionally oxide the product obtained for preparing a product according to claim 1 for which n = 1 or alternatively transforms the product obtained into oxime, for preparing a benzopyran derivative according to claim 1 for which R is defined in 4), when one has obtained the corresponding ketone for which R is a radical defined in 3) in claim 1 (for which m = O and -W-Ar is an optionally substituted phenyl radical), then eliminates if necessary the protective radicals and optionally transforms the product obtained in an addition salt with an acid. 9 - Preparation process according to claim 2, characterized in that a benzopyran derivative of general formula is used:

in its isomeric forms or their mixtures, in which Ri, R and R are defined as in claim 1, and Y ₁ is a bromine or chlorine atom, or a methylsulfonyloxy or p.toluenesulfonyloxy radical. 10 - Process for the preparation of a new benzopyran derivative according to claim 1 for which the radicals Ri, R ₂ and / or R ₃ represent a hydroxy radical, characterized in that the corresponding derivative of Benzopyran according to claim 1 for which the radical R ₁ , R ₂ and / or R ₃ to be transformed represents an alkyloxy radical, then optionally transforms the product obtained into an addition salt with an acid. 11 - Process for the preparation of a new benzopyran derivative according to claim 1, for which R is defined as in claim 1 in 1) or 2) and the radicals Ri, R ₂ and / or Rs represent amino or alkylsulfonamido radicals , or for which the radical R ₁ represents an acylamino radical, characterized in that one carries out the catalytic hydrogenation of the corresponding derivative of benzopyran, according to claim 1, for which the symbol Ri, R ₂ and / or R ₃ to transformer represents a nitro radical, then when we want to obtain a benzopyran derivative for which the radicals Ri, R ₂ and / or R ₃ are defined as above except for representing the amino radical, we transform the derivative benzopyran amine obtained, respectively by sulfonylation or by acylation, then optionally transforms the product obtained into an addition salt with an acid. 12 - Process for the preparation of a new benzopyran derivative according to claim 1, for which R is defined as in claim 1 in 1) and 3), X being a nitrogen atom, characterized in that one makes act a halide of general formula:

in which R ₂ , R ₃ , W, Ar and m are defined as in claim 1 and Hal represents a halogen atom, on a benzopyran derivative of general formula:

in which R ₁ , R and R "are defined as in claim 1, then optionally converts the product obtained into an addition salt with an acid. 13 - Pharmaceutical composition characterized in that it comprises a benzopyran derivative according to claim 1, in the pure state or in the form of a combination with one or more diluents or adjuvants compatible and pharmaceutically acceptable.